Compositions and devices incorporating water-insoluble therapeutic agents and methods of the use thereof

ABSTRACT

Various aspects of the present disclosure provide compositions including a water-insoluble therapeutic agent and a gallate-containing compound. Other aspects provide methods of using such compositions.

RELATED APPLICATIONS

This patent application is a continuation-in-part of U.S. patentapplication Ser. No. 16/408,663, filed May 10, 2019, which applicationis a continuation of U.S. patent application Ser. No. 16/001,514, nowU.S. Pat. No. 10,328,183, filed Jun. 6, 2018, which is a continuation ofU.S. patent application Ser. No. 15/386,662, filed Dec. 21, 2016, nowU.S. Pat. No. 10,016,536, which is a continuation of U.S. patentapplication Ser. No. 14/880,332, filed Oct. 12, 2015, now U.S. Pat. No.9,572,914, which is a continuation of U.S. patent application Ser. No.14/454,325, filed Aug. 7, 2014, now U.S. Pat. No. 9,180,226, the entirecontents of which applications are hereby incorporated by reference.

TECHNICAL FIELD

The present invention generally relates to compositions and devicesincluding a water-insoluble therapeutic agent solubilized in agallate-containing compound and to methods of making and using suchcompositions and devices.

BACKGROUND

Local delivery of a therapeutic agent can be useful in the treatment ofmany medical conditions. Illustratively, local delivery of a therapeuticagent within a body vessel or to a selected portion of internal bodytissue can eliminate or reduce the need for systemic delivery of thetherapeutic agent thus minimizing any potential adverse effect of thetherapeutic agent on areas of the body not needing treatment.

Minimally invasive implantable medical devices, such as balloons,catheters and stents, can provide a platform for delivering therapeuticagents to internal body tissue. For example, balloon catheters or stentsmay be used to deliver a therapeutic agent directly to the target sitewithin a body vessel such as an artery or vein.

One example of a condition that can be beneficially treated by localadministration of a therapeutic agent with a balloon catheter is thedelivery of a therapeutic agent in combination with percutaneoustransluminal coronary angioplasty (PTCA), a technique used to dilatestenotic portions of blood vessels. In such cases, a catheter ballooncoated with the therapeutic agent can be positioned at a blocked lumenor target site during PTCA, and the balloon is inflated causing dilationof the vessel lumen. The catheter balloon is pressed against the vesselwall for delivery of the therapeutic agent to the vessel wall. Theballoon is deflated and the catheter is then removed from the targetsite and the patient's lumen thereby allowing blood to more freely flowthrough the now less restricted lumen.

Although PTCA and related procedures aid in alleviating intraluminalconstrictions, such constrictions or blockages may reoccur in manycases. The cause of these recurring obstructions, termed restenosis, maybe due to the body responding to the surgical procedure. Restenosis ofthe vessel may develop over several months after the procedure, and mayrequire another angioplasty procedure or a surgical bypass operation tocorrect. Proliferation and migration of smooth muscle cells (SMC) fromthe media layer of the lumen to the intimal layer cause an excessiveproduction of extracellular matrices (ECM), which is believed to be oneof the leading contributors to the development of restenosis. Theextensive thickening of tissues narrows the lumen of the blood vessel,constricting or blocking the blood flow through the vessel. Therapeuticagents that inhibit restenosis may be locally delivered during PTCA froma catheter or by placement of a stent configured to continue to releasethe therapeutic agent after the PTCA procedure.

The delivery of the therapeutic agent from coatings in these and otherminimally invasive procedures can be complicated by the need both tohave a coating that is durable during delivery, but which effectivelydelivers the therapeutic agent when implanted in the region where localtreatment is desired. Furthermore, numerous therapeutic agents are notfreely soluble in an aqueous environment. Because natural biologicalenvironments are aqueous, it can occur that a coating containing awater-insoluble therapeutic agent is sufficiently durable during travelto the intended delivery site, but then fails to optimally deliver thetherapeutic agent at the site.

Therapeutic agents may also be useful in dermal applications, forexample when formulated for topical application to the skin. Topicaldrug preparations include, for example, creams, pastes, gels, lotions,ointments, and the like. In general, there are several clinical reasonsfor delivering drugs via the skin. These include treating local diseasesof the skin (e.g., psoriasis), and/or for delivering the drug throughthe skin into the systemic circulation (e.g., nicotine). Althoughattractive, these delivery routes are strongly impeded by the skin'souter layer (epidermis) and in particular by the stratum corneum. Thestratum corneum consists of many layers of dead cells packed tightlytogether to create a densely-packed, hydrophobic barrier. Some drugs,such as corticosteroids are able to penetrate this barrier. However,many drugs are unable to penetrate this barrier. For example, watersoluble drugs do not pass well through such environments. Largermolecules can also be excluded from penetration due to their size.Pharmaceutical scientists have described a number of penetrationenhancers that may be added to creams and gels to assist drug transfer,however this route of administration still can result in low levels ofuptake for most drugs.

Drug movement through the stratum corneum depends in part on thediffusion gradient of the drug across the skin. Although hydrophilic(water soluble) drugs may be formulated at higher concentrations insolution in aqueous gels and creams to create higher diffusiongradients, these drug molecules do not transfer across the epidermis dueto their hydrophilicity. Hydrophobic drugs also present challenges inaqueous formulations because these drugs do not readily dissolve inwater, making higher diffusion gradients difficult or impossible toachieve. Some formulations use a micellar technique to improve aqueousformulations, however known micellar formulations are not optimal.Instead of creating a true solution, where the drug molecules are freeto move within the water, micellar formulations sequester the drugmolecules within micelle structures, limiting the mobility of the drugmolecules and limiting the ability to create high drug gradients acrossthe skin.

Needs thus exist for compositions, coatings, and coated implantablemedical devices which enable the beneficial delivery of awater-insoluble therapeutic agent locally to a site intended fortreatment.

SUMMARY

One aspect of the present disclosure relates to compositions includingat least one water-insoluble therapeutic agent solubilized in a matrixof at least one gallate containing compound. In some embodiments, thegallate containing compound increases the solubility of thewater-insoluble therapeutic agent in an aqueous medium and/or enhancesthe delivery of the water-insoluble therapeutic agent to a vessel walland into the tissue of a patient. In certain embodiments, the gallatecontaining compound and the water-insoluble therapeutic agent arepresent at a weight ratio of between 1 to 40 and 500 to 1 gallatecontaining compound to water-insoluble therapeutic agent. In otherembodiments, the gallate containing compound is epi gallo catechingallate (EGCG), tannic acid or epi catechin gallate.

Another aspect of the present disclosure relates to a medical devicehaving a surface including a coating containing such a compositionand/or having the composition incorporated into at least part of thestructure of the device. In one embodiment, the coating is free of anadditional polymer or non-polymer carrier modifying a rate of release ofthe therapeutic agent from the device upon implantation in the body of apatient.

In certain embodiments, the implantable medical device is an expandabledevice. In other embodiments, the device is a vascular stent, a ureteralstent, a catheter, a balloon, a balloon catheter, an embolic device, astent graft, a wire guide, or a cannula.

The water-insoluble therapeutic agent can be, for example, animmunosuppressive agent, an antiproliferative agent, a microtubulestabilizing agent, a restenosis-inhibiting agent, an inhibitor of themammalian target of rapamycin, an analgesic, or an anesthetic. Incertain embodiments, the water-insoluble therapeutic agent is a taxanecompound, for example, paclitaxel. In other embodiments, thewater-insoluble therapeutic agent is an analgesic and/or an anestheticagent, for example lidocaine.

Another aspect of the present disclosure relates to a method fordelivering a therapeutically effective amount of a water-insolubletherapeutic agent locally to the tissue of a patient. In certainembodiments the method includes contacting a vessel wall of the patientwith a medical device as provided by the present invention andmaintaining the device in contact with the vessel wall for a timesufficient to deliver the water-insoluble therapeutic agent to thetissue of the patient.

In other embodiments, the method includes applying to a patient's skin atopical drug preparation comprising a gallate containing compound and awater-insoluble therapeutic agent in a suitable dosage form for dermaldelivery of the agent to the patient. Suitable forms include, but arenot limited to, sprays, foams, gels, pastes, ointments, creams, lotionsand tinctures. In some embodiments, liquid or semi solid forms of thedrug preparation may be preformulated and then included within a medicaldressing. In some embodiments, the preparation may be nonaqueous. Insome embodiments, solid or semi-solid dosage forms of the drugpreparation may comprise dried combinations of gallate containingcompounds and water-insoluble drugs in the form of a film or pellet,which may be placed on the patient's skin in an area to be treated. Insome embodiments, the drug preparation may be cast as a film or premadein the form of microspheres, and/or may comprise polymers or polymerichydrogel carrier materials such as, but not limited to, polylactic coglycolic acid, polymethyl methacrylate, polyvinyl alcohol, hyaluronicacid, alginate or celluloses.

In other embodiments, the method includes injecting or extruding apharmaceutical preparation comprising a gallate containing compound anda water-insoluble therapeutic agent at an area of the patient to betreated. The preparation may be applied to the patient by injection orextrusion into the patient's body, or outside of the patient's body(e.g., to treat an exterior wound). The preparation is preferablyformulated as a viscous liquid or semi solid, and in some embodimentsmay be formulated as a nonaqueous paste. The preparation is preferablyformulated to controllably release of the therapeutic agent into thepatient at the area to be treated. The preparation is formulated tocontrollably release the agent over a period of time. In someembodiments, the preparation is formulated to controllably release theagent over a period of at least two days, at least seven days, or atleast two weeks. In some embodiments, the preparation may comprise aviscous polymeric liquid such as, but not limited to, polypropyleneglycol, polyethylene glycol, glycerol, labrasol, transcutol, tween orpluronic. In some embodiments, the preparation may comprise a eutecticmixture. Examples of suitable eutectic mixtures include, but are notlimited to, eutectic mixtures of ibuprofen and menthol, and eutecticmixtures of lidocaine and menthol.

In some embodiments, dermal or injectable preparations for use in themethods described above may include additional excipients commonly knownto pharmaceutical scientists.

Another aspect of the present disclosure provides a method for treatinga patient suffering from a disease or condition. One embodiment of themethod includes implanting a medical device provided by the presentinvention in a vessel of a patient for a time sufficient to deliver atherapeutically effective amount of the water-insoluble therapeuticagent to a tissue of the patient. Another embodiment of this methodincludes the delivery of a solution of a water-insoluble therapeuticagent and a gallate containing compound by or in association with amedical device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1(A)-(C) are graphs showing the solubility of amphotericin as afunction of EGCG or Tannic acid concentration. FIG. 1(A) shows theeffect of storage temperature on the solubility for solutions includingEGCG. FIG. 1(B) shows the effect of storage temperature on thesolubility of solutions including Tannic Acid. FIG. 1(C) shows thevariation in amphotericin solubility with pH.

FIGS. 2(A)-(B) are graphs showing the solubility and stability ofcurcumin in solutions of EGCG FIG. 2(A) or tannic acid FIG. 2(B) after 2hrs. and 24 hrs.

FIGS. 3(A)-(D) are graphs showing the solubility and stability ofpaclitaxel in solutions of EGCG (FIG. 3(A) and FIG. 3(C)) or tannic acid(FIG. 3(B) and FIG. 3(D)) at various times and temperatures.

FIGS. 4(A)-(D) are graphs showing the solubility and stability ofdocetaxel in a solution of EGCG (FIG. 4(A) and FIG. 4(C)) or tannic acid(FIG. 4(B) and FIG. 4(D)) at various times and temperatures.

FIG. 5 is a bar chart showing the uptake into and across a monolayer ofmdck cells for docetaxel combined with solubilization agents tween,diblock copolymer or EGCG.

FIG. 6 is a bar chart showing the update into and across a monolayer ofCaco2 cells for curcumin as a micelle or after with EGCG as asolubilization agent. The chart illustrates apical to basolateraltransport (transcellular) and accumulation (intracellular) of curcuminin caco2 cells incubated with either micellar (diblock polymer) or EGCGsolutions of the drug at 250 micrograms/ml.

FIG. 7 is a graph showing the effect of diblock copolymer of the releaseof paclitaxel from EGCG coated balloon catheters. Balloons are coatedwith 30 mg of EGCG and 300 micrograms of paclitaxel. Percentage releaseinto PBS at 37 C is measured by HPLC

FIG. 8 is a bar chart showing the transfer of paclitaxel to a rat aortafrom an EGCG-coated balloon catheter.

FIG. 9 is a bar chart showing the effect of ultrasound on the transferof paclitaxel to the aorta from an EGCG coated catheter.

FIG. 10 is a bar chart showing the transfer of paclitaxel into an arteryusing a diblock copolymer coating.

FIG. 11 is a bar chart showing the transfer of paclitaxel into an arteryfrom a tannic acid-coated balloon catheter.

FIG. 12 is a bar chart showing the uptake of docetaxel into huvec cellsand the effect of ultrasound.

FIG. 13 is a bar chart showing the uptake and transfer of amphotericin Bin Caco2 cells.

FIG. 14 is an illustration show a reaction scheme for the manufacture ofPAMAM dendrimer-crosslinked gallic acid compounds.

FIG. 15 is a bar chart showing the solubility of drugs in tannic acid orEGCG coatings.

FIGS. 16(A)-(B) are graphs showing the solubility and stability ofrapamycin in solutions of EGCG (FIG. 16(A)) or tannic acid (FIG. 16(B))after 2 hrs. and 24 hrs.

FIG. 17 is a graph showing the transfer of rapamycin to an artery wallfrom an EGCG coated balloon catheter.

FIG. 18 is a graph showing the release of finasteride from embospheres(Merit Medical) or PVA foam embolic particles (Cook Medical).

FIG. 19 is a graph showing the effect of EGEC or Tannic Acid on therelease of finasteride from PLGA microspheres.

FIG. 20 is a graph showing the solubilization of finasteride by EGCG.

FIG. 21 is a graph showing the solubilization of finasteride by tannicacid.

FIGS. 22(A)-(B) are graphs showing the uptake of docetaxel FIG. 22(A) orpaclitaxel FIG. 22(B) into pigs bladder tissue following incubation withEGCG or tannic acid solutions of the drugs.

FIG. 23 is a graph showing the uptake of paclitaxel into bladder tissuefollowing incubation with a paste formulation composed ofmethoxypolyethylene glycol with EGCG or tannic acid on either theurothelial or perivesicular surfaces of the bladder tissue.

FIG. 24 is a graph showing the uptake of paclitaxel or docetaxel intobladder tissue following perivesicular application of a paste containingEGCG or tannic acid in a triblock copolymer with methoxypolyethyleneglycol;

FIG. 25 is a graph showing the uptake of paclitaxel or into bladdertissue following perivesicular application of a paste containing EGCG ortannic acid in a diblock copolymer with methoxypolyethylene glycol.

FIG. 26 is a graph showing uptake of paclitaxel by pig skin after sixhours of incubation using different formulations containing paclitaxel(ptx) at 0.6% w/w. The zero mark on the x-axis represents the skinsurface origin (0) so deeper cuts are shown to the right along the xaxis. The following are illustrated: 1—EGCG; 2—Tannic Acid; 3—Plogel;4—PG/ECGC; 5—PG/Tannic Acid; 6—Glaxal Base; and 7—Emulsion.

FIG. 27 is a graph showing uptake of docetaxel by pig skin after sixhours of incubation using different formulations containing docetaxel(dtx) at 0.6% w/w. The origin (0) is the skin surface with deeper cutsgoing to the right on the x axis. The following are illustrated: 1—EGCG;2—Tannic Acid; 3—Plogel; 4—PG/ECGC; 5—PG/Tannic Acid; and 6—Glaxal Base.

FIG. 28 is a graph showing uptake of lidocaine by pig skin after a sixhour incubation using different formulations containing lidocaine at 4%w/w. The origin (0) is the skin surface with deeper cuts going to theright on the x axis. The following are illustrated, 1—EGCG; 2—TannicAcid; 3—Plogel; 4—PG/ECGC; 5—PG/Tannic Acid; 6—Glaxal Base; and7—Eutectic.

FIG. 29 is a graph showing the rate of anesthetic penetration depth ofEMLA and EGCG formulations. Here, pig skin is incubated with EMLA (2.5%Prilocaine and 2.5% lidocaine) or PG:EGCG (60:40) paste containing 5%lidocaine. The following are illustrated: 1) EMLA 0-250 μm; 2) EMLA250-500 μm; 3) EGCG 0-250 μm; and 4) EGCG 250-500 μm.

FIG. 30 is a graph showing uptake of retinoic acid by pig skin after asix hour incubation using different formulations containing retinoicacid at 0.6% w/w. The origin (0) is the skin surface with deeper cutsgoing to the right on the x axis. The following are illustrated: 1—EGCG;2—Tannic Acid; 3—Plogel; 4—PG/ECGC; 5—PG/Tannic Acid; 6—Glaxal Base; and7—Eutectic.

FIG. 31 is a graph showing uptake of amphotericin B by pig skin after asix hour incubation using different formulations containing amphotericinB at 0.6% w/w. The origin (0) is the skin surface with deeper cuts goingto the right on the x axis. The following are illustrated: 1—EGCG;2—Tannic Acid; 3—Plogel; 4—PG/ECGC; 5—PG/Tannic Acid; and 6—Glaxal Base.

FIG. 32 is a graph showing uptake of curcumin by pig skin after a sixhour incubation using different formulations containing curcumin at 0.6%w/w. The origin (0) is the skin surface with deeper cuts going to theright on the x axis. The following are illustrated: 1—EGCG; 2—TannicAcid; 3—Plogel; 4—PG/ECGC; 5—PG/Tannic Acid; and 6—Glaxal Base.

FIG. 33 is a graph showing uptake of Finasteride by pig skin after 6hour incubation using different formulations containing finasteride at0.25% w/w. The origin (0) is the skin surface with deeper cuts going tothe right on the x axis. The following are illustrated: 1—EGCG; 2—TannicAcid; 3—PG/ECGC; 4—PG/Tannic Acid; and 5—Glaxal Base.

FIG. 34 is a graph showing release of paclitaxel or docetaxel fromPG:gallate pastes (60:40) containing EGCG or tannic acid.

FIG. 35 is a graph showing release of retinoic acid, amphotericin B, orcurcumin from PG:gallate pastes (60:40) containing EGCG or tannic acid.

FIGS. 36(A)-(C) are graphs showing release of lidocaine (20%, 15%, 10%,or 5%) from EGCG:Propylene Glycol pastes. The following are illustrated:EGCG (40%)/Propylene Glycol (60%) paste (FIG. 36A); EGCG (30%)/PropyleneGlycol (70%) paste (FIG. 36B); EGCG (20%)/Propylene Glycol (80%) paste(FIG. 36C).

FIGS. 37(A)-(C) are graphs showing degradation of paste pelletsincluding lidocaine (20%, 15%, 10%, or 5%) and EGCG:Propylene Glycol.The following are illustrated: EGCG (40%)/Propylene Glycol (60%) paste(FIG. 37A); EGCG (30%)/Propylene Glycol (70%) paste (FIG. 37B); EGCG(20%)/Propylene Glycol (80%) paste (FIG. 37C).

FIGS. 38(A)-(C) are graphs showing release of lidocaine (20%, 15%, 10%,or 5%) from Tannic Acid:Propylene Glycol pastes. The following areillustrated: Tannic Acid (40%)/Propylene Glycol (60%) paste (FIG. 38A);Tannic Acid (30%)/Propylene Glycol (70%) paste (FIG. 38B); Tannic Acid(20%)/Propylene Glycol (80%) paste (FIG. 38C).

FIGS. 39(A)-(C) are graphs showing degradation of paste pelletsincluding lidocaine (20%, 15%, 10%, or 5%) and Tannic Acid:PropyleneGlycol. The following are illustrated: Tannic Acid (40%)/PropyleneGlycol (60%) paste (FIG. 39A); Tannic Acid (30%)/Propylene Glycol paste(70%) (FIG. 38B); Tannic Acid (20%)/Propylene Glycol paste (80%) (FIG.39C).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purpose of promoting an understanding of the principles of theinvention, reference will now be made to embodiments, some of which areillustrated in the drawings, and specific language will be used todescribe the same. It will nevertheless be understood that no limitationof the scope of the invention is thereby intended. Any alterations andfurther modifications in the described embodiments, and any furtherapplications of the principles of the invention as described herein arecontemplated as would normally occur to one skilled in the art to whichthe invention relates.

In the discussions that follow, a number of potential features orselections of the water-insoluble therapeutic agent, gallate containingcompound, implantable medical device structure, or other aspects, aredisclosed. It is to be understood that each such disclosed feature orfeatures can be combined with the generalized features discussed herein,to form a disclosed embodiment of the present invention.

Definitions

The term “therapeutic effect” as used herein means an effect whichinduces, ameliorates or otherwise causes an improvement in thepathological symptoms, disease progression or physiological conditionsassociated with or resistance to succumbing to a disorder, for examplerestenosis, of a human or veterinary patient. The term “therapeuticallyeffective amount” as used with respect to a therapeutic agent means anamount of the therapeutic agent which imparts a therapeutic effect tothe human or veterinary patient.

The term “water-insoluble” as applied to a therapeutic agent hereinrefers to a therapeutic agent having a solubility in water at 25° C. ofless than 2 milligrams per milliliter (mg/ml). More preferably, thewater-insoluble therapeutic agent has a solubility in water at 25° C. ofless than 1 mg/ml, even more preferably less than 0.1 mg/ml, and incertain embodiments less than 10 micrograms per milliliter (μg/ml).

The term “pharmaceutically acceptable carrier” includes any and allsolvents, dispersion media, coatings, antibacterial and antifungalagents, isotonic and absorption delaying agents, and the like,compatible with pharmaceutical administration. Preferred examples ofsuch carriers or diluents include, but are not limited to, water,saline, dextrose solution, and 5% human serum albumin. Liposomes andnon-aqueous vehicles such as fixed oils may also be used. Supplementaryactive compounds can also be incorporated into the compositions.

The term “solubilized” describes the condition in which awater-insoluble therapeutic agent, for example paclitaxel, is dissolvedin a solvent, for example a matrix of gallate containing compound.“Solubilization” is the presence of the agent in a non-particulate formwhich is typically at the single molecule level. The solubilized agentcan be present in a liquid solution such as in aqueous media or in anorganic solvent. Alternatively, the solubilized agent is present in anon-particulate form in a solid or semi-solid matrix composed of anothernon liquid material. In some cases the solubilised agent may be presentin the center of nanoparticles or micelles suspended in aqueous media.

“The term “eutectic” refers to a mixture of substances that either meltsor solidifies at a single temperature that is lower than the meltingpoints of the separate constituents.

Compositions

One aspect of the present invention relates to compositions including atleast one water-insoluble therapeutic agent and at least one gallatecontaining compound. In certain embodiments, the composition includes anaqueous solvent, for example water or a pharmaceutically acceptablebuffer. In these embodiments, the presence of the gallate containingcompound results in an aqueous solution in which the water-insolubletherapeutic agent is dissolved in the aqueous solvent at a higherconcentration that would be possible under the same conditions if thegallate containing compound was not present.

Another embodiment relates to compositions including at least onewater-insoluble therapeutic agent solubilized within a matrix of atleast one gallate containing compound. Such compositions, termed “solidsolutions,” do not include an aqueous solvent. Instead, thewater-insoluble therapeutic agent is dissolved at a molecular levelwithin a matrix of the gallate containing compound, which acts as asolvent. Yet another embodiment relates to compositions formed by theaddition of an aqueous solvent to the solid solution. Such compositionscan contain the water-insoluble therapeutic agent is dissolved in theaqueous solvent as well as a nanoparticulate form for thewater-insoluble therapeutic agent.

In some embodiments, the gallate containing compound increases thesolubility of the water-insoluble therapeutic agent when the compositionis applied to an aqueous medium, for example when administered to ahuman or veterinary patient; enhances the delivery of thewater-insoluble therapeutic agent to and/or across a vessel wall andinto the tissue of the patient; and/or enhances the dermal uptake of thewater-insoluble therapeutic agent when applied to a patient's skin. Inyet other embodiments the gallate containing compound increases thecellular uptake of the water-insoluble therapeutic agent. In otherembodiments the drug is partly or fully dissolved in the solid phase ofthe gallate containing compound so that in an aqueous environment, thedrug is released from the formulation as the gallate containing compounddissolves.

The gallate containing compound may be a compound such as, but notlimited to, epi gallo catechin gallate (EGCG) or tannic acid. Otherpreferred compounds include natural and synthetic compounds containinggallates. Yet other preferred compounds include compounds that containthe chemical moieties of gallate, catechin, tannin, or similarpolyphenol moieties, including naturally derived compounds, as well aspolymers that have been synthetically modified and covalently attachedto these moieties.

In other embodiments, gallate containing compounds include, but are notlimited, to the tannins, catechin gallates, the querglanins, galloylarbutin, theaflavine gallate or digallate galloylbergenin,camelliatannin, theasinensin, procyanidingallate, galloylsilibin,trihydroxystillbene-4-6-galloyl-glocopyranoside, comuside. In certainembodiments, these compounds are characterized by high levels of H-bonddonor and acceptor sites along with benzene or lactone ring structures.In other embodiments, gallate containing compounds include similarmolecules to EGCG or tannins that do not specifically contain thetrihydroxy benzoate group of the gallate but have very similarstructures to the gallate Examples of such compounds include, but notlimited to, the mangiferines, the quercetins, especially, quercetin 3glucopyranoside, quercetin glucoside, quercetin galactoside, quercetinmeritrin, hesperidin methylchalcone, isobutrin, hypolactin glucoside,rutin and procyanadin and proanthocyandin.

In certain embodiments, the weight ratio of gallate containingcompound:water-insoluble therapeutic agent in the composition is in therange of 200:1 to 1:1 or 200:1 to 5:1 or 200:1 to 10:1 or 200:1 to 30:1or 200:1 to 50:1 or 100:1 to 1:1 or 100:1 to 5:1 or 100:1 to 10:1, or100:1 to 30:1 or 100:1 to 50:1 or 50:1 to 1:1 or 50:1 to 5:1 or 10:1 to1:1 or 10:1 to 5:1 or 1:1 to 1:2 or 1:1 to 1:5 or 1:40 to 500:1 or 1:20to 400:1 or 1:10 to 200:1 or 1:1 to 200:1 or 1:40 to 200:1 or 1:20 to200:1 or 1:10 to 500:1. When more than one gallate containing compoundis present, the above ranges can apply to the ratio of the weight ofeach individual gallate containing compound to weight of thewater-insoluble therapeutic agent or to ratio of the total weight of thegallate containing compounds present to the weight of the water-solubletherapeutic agent. The weight ratio of gallate containing compound towater-insoluble drug is such that a solution of the water-insolubletherapeutic agent in the gallate containing compound is formed.

In other embodiments, the composition includes the gallate containingcompound in an amount that increases the solubility of a water-insolubletherapeutic agent in the composition by 10, 20, 30, 40, 50, 75, 100,125, 150, 200, 300 or 400 percentage in an aqueous medium compared to anotherwise identical composition that does not include the gallatecontaining compound.

In yet other embodiments, the composition includes the gallatecontaining compound a concentration of between 10 and 50, or 20 and 50,or 30 and 50, or 40 and 50 mg/ml and the water-insoluble therapeuticagent, for example paclitaxel or docetaxel, solubilized at aconcentrations of at least 400, 500, 600, 700, 800, 900 or 1000micrograms/ml.

In some embodiments, a composition for the treatment of a medicalcondition comprises a topical drug preparation comprising a gallatecontaining compound and a water-insoluble drug, where the gallatecontaining compound is present in an amount effective in increasing thedermal uptake of the drug. In some embodiments, the gallate containingcompound is selected from the group consisting of epi gallo catechingallate and tannic acid. In some embodiments, the drug is selected frompaclitaxel, docetaxel, amphotericin, curcumin, retinoic acid,finasteride, and lidocaine. In some embodiments, the drug has amolecular weight greater than 500 Daltons. In some embodiments, thegallate containing compound is present in an amount by weight equal toor greater than the amount by weight of the water-insoluble drug. Insome embodiments, the weight ratio of gallate containingcompound:water-insoluble drug is in the range of 200:1 to 1:1, 200:1 to5:1, 200:1 to 10:1, 200:1 to 30:1, 200:1 to 50:1, 100:1 to 1:1, 100:1 to5:1, 100:1 to 10:1, 100:1 to 30:1, 100:1 to 50:1, 50:1 to 1:1, 50:1 to5:1, 10:1 to 1:1, 10:1 to 5:1, 1:1 to 1:2, or 1:1 to 1:5.

Suitable topical drug preparation forms comprise creams, pastes, gels,ointments, and other suitable forms for topical application. In someembodiments, the topical preparation comprises a preblended solid orsemi solid matrix of the gallate containing compound and the drug. Insome embodiments, the composition further comprises a solubilizingexcipient such as propylene glycol. In some embodiments, the topicalpreparation comprises a eutectic solution, for example a eutecticsolution of lidocaine and menthol, or a eutectic solution of ibuprofenand menthol. In some embodiments, the topical drug preparation is a dry,or nonaqueous preparation. In some embodiments, the gallate containingcompound and the drug are predispersed in one of a membrane, a hydrogel,an electrospun film, or a skin dressing.

In certain embodiments, a composition for the treatment of a medicalcondition comprises a nonaqueous pharmaceutical preparation comprising agallate containing compound and a water-insoluble drug, where thepreparation is formulated to form a partially water-insoluble mass whenplaced in an aqueous medium, that gradually releases the drug into theaqueous medium in a controlled manner. Such preparations may be useful,for example, in methods involving local delivery of a drug within apatient's body, or on an exterior wound of a patient's body. In someembodiments, the gallate containing compound is selected from the groupconsisting of epi gallo catechin gallate and tannic acid. In someembodiments, the drug is selected from paclitaxel, docetaxel,amphotericin, curcumin, retinoic acid, finasteride, and lidocaine. Insome embodiments, the composition further comprises a solubilizingexcipient, for example an excipient selected from the group consistingof glycerol, pluronic, propylene glycol, and polyethylene glycol.

In some embodiments, the preparation is formulated to release the druginto the aqueous medium over a period of at least two days, over aperiod of at least seven days, or over a period of at least two weeks.In some embodiments, the gallate containing compound is present in anamount effective in increasing the solubility of the water-insolubledrug in an aqueous medium. In some embodiments, the gallate containingcompound is present in an amount by weight equal to or greater than theamount by weight of the water-insoluble drug. In some embodiments, thepreparation is formulated as a viscous liquid or semi solid, and in someembodiments may be formulated as a paste.

Water-insoluble therapeutic agents within the scope of the presentembodiments include water-insoluble antiproliferative agentsimmunosuppressive agents, restenosis-inhibiting agents, anti-canceragents, analgesics/antipyretics, anesthetics, antiasthmatics,antibiotics, antidepressants, antidiabetics, antifungal agents,antihypertensive agents, anti-inflammatories, antineoplastics,antianxiety agents, sedatives/hypnotics, antianginal agents, nitrates,antipsychotic agents, antimanic agents, antiarrhythmics, antiarthriticagents, antigout agents, thrombolytic agents, hemorheologic agents,anticonvulsants, antihistamines, agents useful for calcium regulation,antibacterial agents, antiviral agents, antimicrobials, anti-infectives,bronchodilators, steroids and hormones.

Non-limiting examples of such water-insoluble therapeutic agents includelidocaine, prilocaine, finasteride, dutasteride, enzalutamide,bicalutamide, abiraterone, tamsulosin, sildenafil-base, tadalafil,doxorubicin, camptothecin, etoposide, mitoxantrone, cyclosporine,epothilones, napthoquinones, paclitaxel, docetaxel, carbitaxel, retinoicacid, limus based drugs (e.g. rapamycin, sirolimus), methotrexate,vincristine, vinblastine, gemcitabine, statins (for exampleatorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin,rosuvastatin and simvastatin), steroids (for example cortisteroids,prednisilone and dexamethazone), mitomycin, amphotericin, curcumin andderivatives or analogues of these agents.

Preferred water-insoluble therapeutic agents include water-insolubleantiproliferative agents, immunosuppressive agents,restenosis-inhibiting agents. In particular embodimentsantiproliferative agents or immunosuppressive agents that arerestenosis-inhibiting agents are utilized, which can be effective toinhibit restenosis of a vessel when applied to the inner wall of thevessel. In this regard, “restenosis-inhibiting” includes preventing orreducing the extent of restenosis. The inhibition of restenosis may beobserved after a procedure in which the vessel wall is injured due todilatation, for example during dilatation with a balloon of a ballooncatheter and/or by expansion of a stent.

The water-insoluble restenosis-inhibiting agent may be a microtubulestabilizing agent such as paclitaxel, docetaxel, a paclitaxel analog, ora paclitaxel derivative or other taxane compound; a macrolideimmunosuppressive agent such as sirolimus (rapamycin), pimecrolimus,tacrolimus, everolimus, zotarolimus, novolimus, myolimus, temsirolimus,deforolimus, or biolimus; an antiproliferative agent; a smooth musclecell inhibitor; an inhibitor of the mammalian target of rapamycin (mTORinhibitor); or a mixture of two, or two or more of any of these. Theseor other water-insoluble restenosis-inhibiting agents, including eachagent or agent type identified herein, more preferably have a solubilityin water at 25° C. of less than 1 mg/ml, even more preferably less than0.1 mg/ml, and in certain embodiments less than 10 micrograms/ml.Paclitaxel, docetaxel, sirolimus, pimecrolimus, tacrolimus, everolimus,zotarolimus, novolimus, myolimus, temsirolimus, deforolimus, andbiolimus are preferred water-insoluble restenosis-inhibiting agents foruse herein (each known to have a water solubility of less than about 10micrograms/ml).

The compositions of the present invention include those that may beadministered by oral, parenteral (e.g., intramuscular, intraperitoneal,intravenous, ICV, transcatheter arterial chemoembolization,intracistemal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration.

Another embodiment of the present invention provides a composition,including the one or more water-insoluble therapeutic agent(s)solubilized in a matrix of one or more gallate containing compound(s),where the composition is encapsulated in microparticles, for example,polymeric microparticles. The microparticles can be biodegradable ornonbiodegradable microparticles. Such microparticles can be delivered toa patient by the delivery means listed above and allow for the deliveryof the water-insoluble therapeutic agent(s) by elution from themicroparticles or as a result of biodegradation of the microparticles.

Nonbiodegradable polymers that can be used to prepare suchmicroparticles include, but are not limited to, cellulose acetate,cellulose nitrate, silicone, polyethylene terephthalate, polyurethane,polyamide, polyester (e.g. Nylon), polyorthoester, polyanhydride,polyether sulfone, polycarbonate, polypropylene, high molecular weightpolyethylene, and polytetrafluoroethylene, or mixtures of these.Biodegradable polymers that can be used include, but are not limited topolylactic acid (PLA), polyglycolic acid (PGA), poly(lactic-co-glycolicacid) (PLGA), polyanhydride, polycaprolactone, polyhydroxybutyratevalerate, or mixtures of these.

In certain embodiments, the compositions containing the water-insolubletherapeutic agent and the gallate containing compound are free, or“substantially free”, of another compound, such as an emulsifier, oil,triglyceride matrix, lipid or other solubilizing agent or carrier, inwhich the water-insoluble therapeutic agent exhibits increasedsolubility. As applied to the present embodiments, the compositions areconsidered to be substantially free of such compounds as long as theadditional compounds do not alter the solubility of the water-insolubletherapeutic agent by more than 1 percentage. In other embodiments, theadditional compounds do not alter the solubility of the water-insolubletherapeutic agent by more than 10, 5 or 2 percentage.

Medical Devices

Other aspects of the present disclosure relate to medical devicesincorporating a releasable component including at least onewater-insoluble therapeutic agent solubilized within a matrix of atleast one gallate containing compound, and to methods for thepreparation and use of such medical devices. In certain embodiments, themedical devices are coated with or otherwise contain the compositions asdisclosed above.

In one embodiment, the medical device may be any of a wide variety ofdevices having an implantable medical device structure sized and shapedfor temporary or permanent implantation in a human or veterinarypatient. Medical devices having structures implantable in a bodilypassage will often be used. The bodily passage may for example be apassage of the alimentary system, the urogenital system, the biliarysystem, or the cardiovascular system. Medical devices including a devicestructure implantable in the cardiovascular system are preferred,including for example those implantable in a vessel or chamber of thecardiovascular system of a human or veterinary patient through whichblood travels. The passage may for example be a tubular passage such asan artery or vein, or may be a larger chamber such as a ventricle oratrium of the heart. Implantable medical devices that include structuresthat span or bridge between cardiovascular or other bodily passages arealso contemplated. The implantable medical device can be adapted to beentirely or only partially implanted in a cardiovascular passage orother bodily passage. Other embodiments cover the use of gallatecontaining compounds and water-insoluble drug solutions or suspensionswith other medical devices such as, but not limited to, tumor resectiontools, surgical operation instruments, specialized injection devices,access catheters, robotic surgical systems.

The releasable component may be incorporated into the structure of themedical device and/or be present in a coating on one or more surface ofthe device. By way of example, the medical device can be or include acatheter, a wire guide, a stent, a coil, a needle, a graft, a filter, aballoon, a cutting balloon, a scoring balloon, a weeping (perfusion)balloon, or any combination of these. In other embodiments the device isa solid or semi-solid material that releases the water-insoluble drugand gallate containing compounds locally as a drug solution orsuspension. Such devices include, but are not limited to, polymericmaterials as films, pastes, micro and nanoparticles.

In some preferred embodiments herein, the implantable medical devicewill be or include a balloon catheter, such as an angioplasty ballooncatheter, a weeping or infusion balloon, a scoring balloon catheter or acutting balloon catheter.

In other embodiments herein, the implantable medical device will be orinclude a stent. Such a stent may for example be a force-expandablestent, such as a balloon-expandable stent, or a self-expanding stent.The stent may be made from any one of numerous metals and alloys,including those identified hereinabove. The structure of the stent maybe formed in a variety of ways to provide a suitable intraluminalsupport structure having an outer surface for contact with the vesselwall upon implantation and an inner surface that faces the lumen of thevessel and that can be generally opposite the outer surface. Forexample, the stent may be made from a woven wire structure, a laser-cutcannula, individual interconnected rings, or another pattern or design.In these or other constructions, the stent can include a plurality ofstruts each having an outer surface for contact with the vessel wall andan inner surface for facing the lumen of the vessel.

In certain embodiments the stent may be configured in the form of one ormore self-expanding “Z-stents” or Gianturco stents, each of which maycomprise a series of substantially straight segments interconnected by aseries of bent segments. The bent segments may comprise acute bends orapices. The Gianturco stents are arranged in a zigzag configuration inwhich the straight segments are set at angles relative to each other andare connected by the bent segments. In other embodiments, the stent maybe formed from a slotted tube generally comprising a series oflongitudinally-adjacent segments and a patter of connecting segmentsdisposed there between. Such stents may be force-expandable, such asballoon-expandable, or self-expanding, as discussed above.Self-expanding stents of this type can be made of a resilient metal,preferably a superelastic metal alloy such as a superelasticnickel-titanium (Ni—Ti) alloy, as occurs for example in the ZILVER®nitinol stent commercially available from Cook Medical.

Any stent discussed above or elsewhere herein can have a stent surfacecarrying the releasable component as discussed herein, either as thesole coating carried by the stent surface, or in combination with one ormore additional coatings positioned underneath and/or overtop the layercontaining the releasable component. As well, surfaces of the stent notcarrying the releasable component may optionally be bare (uncoated), ormay carry one or more different coatings. Additionally, where the stentis mounted on a balloon of a balloon catheter for delivery, the surfaceof the balloon may carry the releasable component and potentially otherlayer(s) as described herein, and/or the surface of the stent may carrythe releasable component and potentially other layer(s) as describedherein. The practice of these and other variants will be within thepurview of those of ordinary skill in the art in view of the teachingsherein.

Another device structure of interest is a covered stent, such as thestents described in U.S. Pat. No. 8,192,479 and in U.S. PatentPublication Number US20100168837, the contents of both of which areincorporated by reference. Such devices allow for delivery of abioactive from a surface in contact the vessel wall while maintainingdownstream perfusion.

When the compositions are present in a coating on a surface of thedevice, the composition may constitute greater than 50, 75, 90, 95 or 99percentage by weight of the coating. In certain embodiments, thecoatings include less than about 5, 2, 1, 0.5, 0.1, 0.05 or 0.01percentage by weight of materials other than the water-insolubletherapeutic agent and the gallate containing compound. In otherembodiments, the coatings include less than about 5, 2, 1, 0.5, 0.1,0.05 or 0.01 percentage by weight of materials, such as polymers orother non-polymer carriers, that alter the release rate of thewater-insoluble therapeutic agent.

Preferred water-insoluble therapeutic agents used in conjunction withmedical devices include water-insoluble antiproliferative agents,immunosuppressive agents, and restenosis-inhibiting agents. Particularlypreferred are water-insoluble restenosis-inhibiting agents, such asthose described above. In certain preferred embodiments, paclitaxel isthe only therapeutic agent included in combination with the device.

The water-insoluble therapeutic agent can be incorporated in the deviceat any suitable level. Typically, when coated onto a device such as astent or a balloon, the water-insoluble therapeutic agent will beincorporated at a level of 0.001 to 1000 micrograms per mm², or 0.01 to1000 micrograms per mm², or 0.1 to 1000 micrograms per mm², or 0.1 to100 micrograms per mm², and in certain preferred forms 0.1 to 10micrograms per mm² or 0.5 micrograms per mm² to 3 micrograms per mm², orin the range of 0.5 micrograms per mm² to 2 micrograms per mm² of thecoated surface. Where two or more therapeutic agents are included in thecoating, the above-recited levels can apply to the combined weight ofall the therapeutic agent(s), or to the therapeutic agents individually.It will also be understood that the coating may contain variations inthe level of therapeutic agent in different regions of the coatingeither due to manufacturing variances or intentional design criteria.Thus, the present invention contemplates coatings in which the level oftherapeutic agent(s) is substantially uniform over the entire areacovered by the coating, or in which the level of therapeutic agent(s)differs substantially in one area of the coating as compared to anotherarea covered by another area of the coating. In certain preferredembodiments, paclitaxel is incorporated at a level in the range of 1microgram per mm² to 10 micrograms per mm², or in the range of 2micrograms per mm² to 6 micrograms per mm², or in the range of 0.5micrograms per mm² to 3 micrograms per mm², or in the range of 0.5micrograms per mm² to 2 micrograms per mm² either as the onlytherapeutic agent in the coating or in combination with one or moreadditional therapeutic agents. In particularly beneficial implantablemedical devices of the invention, such paclitaxel-containing coatingsare carried on a surface of a stent, including for example any stentdescribed herein, and/or on a surface of a balloon of a ballooncatheter, including for example any balloon catheter described herein.

The water-insoluble therapeutic agent will typically be incorporated inthe device in a therapeutically effective amount. In this regard, itwill be understood that where the therapeutic agent is arestenosis-inhibiting agent, the restonosis-inhibiting agent will beincorporated in the coating in an amount that is effective to inhibitrestenosis when the implantable medical device (e.g. a balloon or stent)is deployed so as to deliver the therapeutic agent from the implantablemedical device to a wall of the artery, vein or other vessel or passagethat is being treated by the device. As will be recognized, the level ofa therapeutic agent that will be therapeutically effective will vary inaccordance with the particular therapeutic agent in use, the implantablemedical device in use, the implant site, the condition to be treated,the composition of the coating including the therapeutic agent, andother potential factors. Through routine experimentation in view of thedisclosures herein the achievement of a therapeutically effective amountof the water-insoluble therapeutic agent will be within the purview ofthose ordinarily skilled in the field.

The gallate containing compound(s) is included in the device in anamount effective to form a matrix of gallate containing compound(s)containing solubilized water-insoluble therapeutic agent. In certainembodiments, the weight ratio of gallate containing compound(s) to thewater-insoluble therapeutic agent in the device is in the range of 200:1to 10:1 or 200:1 to 30:1 or 200:1 to 50:1 or 100:1 to 10:1, or 100:1 to30:1 or 100:1 to 50:1 or 1:40 to 500:1 or 1:20 to 400:1 or 1:10 to 200:1or 1:1 to 200:1 or 1:40 to 200:1 or 1:20 to 200:1 or 1:10 to 500:1. Whenmore than one gallate containing compound is present, the above rangescan apply to ratio of the weight of each individual gallate containingcompound to weight of the water-insoluble therapeutic agent or to ratioof the total weight of the gallate containing compounds present to theweight of the water-soluble therapeutic agent.

In embodiments in which the releasable component is contained within orin a layer coating the implantable medical device, the gallatecontaining compound(s) are observed to increase the amount ofwater-insoluble therapeutic agent released when implanted, by 10, 20,30, 40, 50 75, 100, 125, 150, 200, 300 or 400 percentage as compared toa device that is identical except for the absence of the gallatecontaining compound(s).

In certain other embodiments, the gallate containing compound(s) areobserved to increase the delivery of the water-insoluble therapeuticagent across a vessel wall and into the tissue of the patient. Theincrease in the amount of the water-insoluble therapeutic agentdelivered to the tissue of the patient from a device including thegallate containing compound(s) may depend upon a number of factors, suchas the nature of the vessel in which the composition is placed or deviceis implanted, as well as the environment within the vessel and theconstruction of the implantable device.

However, the increase in the amount water-insoluble therapeutic agentdelivered through a vessel wall may be characterized in an ex vivo assayin which the implantable device is placed in a section of theappropriate vessel and incubated in a buffer solution for a fixed time.In one such assay, a device, for example, is placed in a section ofporcine ureter, which is hydrated in a Phosphate Buffered Saline buffer.The ureter is incubated in a closed container for a fixed time, forexample 5 minutes at 37 deg. C. After the incubation period, thewater-insoluble therapeutic agent present in the ureter tissue isextracted using an extraction solution, such as an enzyme solution,organic solvent, organic/aqueous mixture, or acidified mixture. Theextraction solution used is dependent on the water-insoluble therapeuticagent being extracted. The amount of water-insoluble therapeutic agentpresent in the ureter and in the device is determined using, forexample, an appropriate HPLC method.

In certain embodiments, the claimed devices include gallate containingcompound(s) sufficient to increase the amount of water-insolubletherapeutic agent delivered, as measured by this assay, by at least 5%,10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%, 100%, 150% or 200% compared tothe amount of water-insoluble therapeutic agent delivered, under thesame conditions, from an otherwise identical device that does notinclude the gallate containing compound(s). In other embodiments, thedevices include gallate containing compound(s) sufficient to increasethe amount of water-insoluble therapeutic agent delivered, as measuredby this assay, within a period of 1, 5, 15, 30, 60, 120, 300, 500 or1000 minutes by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%,100%, 150% or 200%. In yet other embodiments, the claimed devicesinclude an amount of gallate containing compound(s) sufficient toincrease the amount of water-insoluble therapeutic agent delivered, asmeasured by this assay, within a period of 1, 5, 15, 30, 60 or 120 daysby at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 70%, 100%, 150% or200%.

In certain embodiments, the gallate containing compound(s) is effectiveto deliver a therapeutically effective amount of the water-insolubletherapeutic agent to patient tissue in a time period of about 5 minutesor less after implantation of the implantable medical device. Morepreferably, such time period is about 3 minutes or less, even morepreferably about 2 minutes or less, and most preferably about 1 minuteor less, e.g. in the range of about 20 seconds to about 1 minute. Suchembodiments configured for relatively rapid delivery are especiallybeneficial when the releasable component is carried by a surface of atemporarily implantable medical device structure, for example a balloonof a balloon catheter, including any balloon catheter and in any coatingarrangement described herein.

In those embodiments in which the releasable component is contained as acoating layer, any of a wide variety of coating patterns may be used toconstitute a material coat on the medical device. The coating layer canbe directly adhered to a surface of an implantable structure of themedical device and provide an outermost surface over the implantablestructure, and/or to constitute the entirety of the overall materialcoat on the implantable structure. In other embodiments, an overallmaterial coat adhered to the implantable structure of the medical devicecan include one or more different coatings positioned underneath thelayer including the releasable component (e.g. as in a polymeric orother primer coating, or a different therapeutic agent coating, adhereddirectly to the surface of the medical device), one or more differentcoatings positioned overtop the layer including the releasable component(e.g. as in a polymeric or other protective or diffusion barriercoating), or both. As well, there may be one or more different coatingsadjacent the layer including the releasable component, and/or multiplelayers including the releasable component may be carried by theimplantable medical device at locations discrete from one another. Thelayer including the releasable component may be present in anaperture(s) such as a well(s), groove(s) or hole(s) defined in theimplantable medical device (e.g. in a stent) or may partially coat orcompletely coat the implantable medical device or a given surface (e.g.inner, outer or side surface) of the implantable medical device. Theseand other overall device coating arrangements can be utilized.

The layer including the releasable component can be carried by anysuitable surface of the implantable medical device structure. The layerincluding the releasable component can be carried by, and in someembodiments only by, a surface or surfaces of the implantable medicaldevice configured for contact with patient tissue when the device isimplanted. For example, in some embodiments the layer including thereleasable component is carried by a surface of a balloon of a ballooncatheter, or by a surface of a stent, which is configured for contactwith a wall of a vessel when the balloon is implanted (usuallytemporarily) or when the stent is implanted (usually permanently). Inparticular embodiments, in the case of a balloon of a balloon catheterwhich inflates to provide a substantially cylindrical outer surface asdiscussed above, the layer including the releasable component is carriedby such substantially cylindrical outer surface, either partially orcompletely covering the substantially cylindrical surface. In the caseof a stent having an outer surface as discussed above, the layerincluding the releasable component can be carried by the outer surface,either partially or completely covering the outer surface.

The layer including the releasable component and any other coatinglayers present can be incorporated as a part of the implantable medicaldevice by dipping the uncoated device into a solution containing asolvent, the water-insoluble therapeutic agent and the gallatecontaining compound. The solvent is then removed, for example byevaporation, leaving a coating of the water-insoluble therapeuticcompound in a matrix of the gallate containing compound.

The layer including the releasable component can be constituted entirelyof the water-insoluble therapeutic agent and gallate containingcompound(s), or may, for example, include a biostable polymer, where thepolymer remains attached to the device structure as releasable componentis released. Alternatively, or in addition to the biostable polymer,this layer may include a bioabsorbable polymer. Such a polymer layer caninclude a polymeric matrix, e.g. made using a suitable polymer asidentified herein, and in certain forms will be a porous layer thatreleasably contains an admixture including the water-insolubletherapeutic agent and gallate containing compound(s) in the poresthereof.

In other embodiments, the releasable component can be incorporated intomicrospheres, for example, biostable or biodegradable microspheres. Suchmicrospheres can be suspended in a fluid or may be coated onto thesurface, or contained within, an implantable device.

In certain aspects, a coated medical device as described herein,preferably comprising a stent and/or balloon catheter carrying thereleasable component, can be configured to, and used to, treat anysuitable body passage in a manner including release of thewater-insoluble therapeutic agent to the wall tissue of the bodypassage. The body passage may for example be a vein, artery, biliaryduct, ureteral vessel, body passage or portion of the alimentary canal.A coated medical device as described herein may be used to treat acoronary artery, carotid artery, or a peripheral artery or vein,including as examples a renal artery or vein, iliac artery or vein,femoral artery or vein, popliteal artery or vein, subclavian artery orvein, intercranial artery or vein, aorta, vena cava, or others. Inpreferred embodiments, the coated medical devices will treat or preventstenosis or restenosis in a body passage such as any of those identifiedherein, although treatment of other conditions is contemplated for otherembodiments of the invention. In certain embodiments, the coated medicaldevice is configured and used to treat a narrowing of a peripheralartery or vein.

In another embodiment, the gallate containing compound, for example EGCGor tannic acid, is encapsulated in polymeric materials along with ahydrophobic drug so as to allow for enhanced drug release properties.Such technology also allows for the enhanced uptake of the drug at apreferred implantation site. The gallate containing compound can beincorporated into polymeric microspheres along with taxanes likepaclitaxel or docetaxel and a controlled release of the EGCG wasobserved.

In one embodiment, polymeric microspheres containing the gallatecontaining compound and drugs such as paclitaxel or docetaxel areinjected into the body where a slower release of drug is preferred. Forexample the microspheres can be injected locally to treat diseases suchas rheumatoid arthritis or uterine fibroids. In embolic treatments, themicroparticles can block blood supply and an EGCG or tannic acidstimulated release of paclitaxel or docetaxel can provide for a strongantiproliferative therapy (chemoembolism). Polymeric blends can includehydrophobic polymers such as polylactic acid, polyglycolic acid orpolycaprolactone, polyanhydrides or copolymers (e.g. PLGA). The gallatecontaining compound can also be incorporated into hydrophilic polymerssuch as chitosan, polyvinyl alcohol, alginate and hyaluronic acid.

In another embodiment, the coencapsulation of the hydrophobic drug andthe gallate containing compound in the polymeric matrix accelerate therelease of the drug. In other embodiments, polymer-gallate containingcompound-drug combinations are coated onto an implant for localizedapplication.

In yet further embodiments, drugs that are poorly taken up by the gut(due to reasons such as low solubility, or because they are substratesof drug efflux proteins in the gut) are rendered orally available byusing formulations of the gallate containing compound and the drugs. Forexample, EGCG is stable in acid solutions and unaffected by the acidenvironment of the stomach. In one such embodiment, EGCG enhances theuptake of drugs into gut cells and allows the drugs to pass through thecells into the blood stream before drug efflux proteins can interactwith the compounds to efflux them back into the gut.

In another embodiment, gallate containing compound-drug solutions areinjected directly into the body to allow for preferred localization ofthe drug at a required site of action. Once at the site, enhanced tissueaccumulation of the drug can also occur. For example docetaxel and EGCG(or tannic acid) solutions may be infused or injected into the bladder,synovial joint, eye, tumor, brain, subcutaneous to treat cancer,arthritis, angiogenic disease such as retinopathy or psoriasis orneurological disease such as multiple sclerosis. These applications aresupported by observations that EGCG and tannic acid increase the uptakeof drugs, for example taxanes, into cells and tissues such as thebladder and into tumor cells. Alternatively, an amphotericin and EGCGsolution might be injected directly into a fungal mass in the lung.Alternatively the solutions may be injected into the blood stream ofperitoneal cavity for systemic delivery of the drug.

In yet other embodiments, creams, pastes, or gels containing gallatecontaining compound(s) and hydrophobic drug(s) are placed on the skin toallow for transdermal delivery of the drugs. For example the drugamphotericin might be applied this way to treat either fungal infectionsor leishmaniasis. The skin application of such formulation may beaugmented by a systemic or oral formulation of the hydrophobic drug(e.g. amphoterecin) with a gallate containing compound.

In other embodiments, neurotoxic drugs are used on gallate containingcompound-coated catheters so that upon insertion in the renal artery thecatheter releases the drugs into and then through the artery wall.Applied drugs can include taxanes, vinca alkaloids, platinum baseddrugs, rapamycin based drugs as well as other drugs known to beneurotoxic.

In another embodiment, the coated catheters are used along with radiofrequency ablation fixtures and are inserted into the renal artery toablate the nerves around that artery. Other techniques such as HIFU orcryotherapy may be used for the same purpose. In yet another embodiment,microneedle laden catheters are used to inject compositions containingneurotoxin drugs and gallate containing compound(s) through the renalartery wall. Such coated catheter systems can be used to deliversubstantial levels of neurotoxic drugs to blood vessels and to allow thetransfer of drug through the vessel wall into the surrounding spacecontaining nerve bundles.

The following examples illustrate the present invention. The examplesand embodiments described herein are for illustrative purposes only andmodifications or changes in light thereof will be suggested to oneskilled in the art without departing from the scope of the presentinvention.

EXAMPLES Example 1. Solubility of Amphotericin as a Function of EGCG orTannic Acid Concentration, Effect of Temperature, pH and Stability at 24Hours

Amphotericin and either EGCG or tannic acid were dried down fromacetonitrile (EGCG) or methanol (tannic acid) solutions at various drugto EGCG or tannic acid ratios. PBS (EGCG) or water (tannic acid) wasadded and the final solution filtered through a 0.22 micron filter toremove any particulates. The solutions were analyzed for drugconcentration using HPLC.

EGCG solubilised amphotericin up to a maximum concentration of 200 mgper ml EGCG with amphotericin at approximately 1800 microgram per ml.The solutions were stable for 24 hours (FIG. 1a ). Tannic acidsolubilised amphotericin up to a maximum concentration of 500 mg per mlTannic acid with amphotericin at approximately 5700 microgram/ml.Solutions were stable for 24 hours (FIG. 1(b)). There was some effect oftemperature on solubility levels with a small reduction at 100 and 200mg/ml and a large reduction at 500 mg/ml for both 37° C. and 50° C.compared to 23° C. There was no effect of pH on amphotericin solubilityin Tannic acid solutions (FIG. 1(c)).

The free solubility of amphotericin is approximately 1-10 micrograms/mlin water. However, the presence of EGCG or tannic acid significantlyincreases the solubility of amphotericin.

Example 2. Solubility of Curcumin as a Function of EGCG or Tannic AcidConcentration, Effect of Temperature and 24 Hour Stability of Solutions

Curcumin and EGCG or tannic acid were dried down from acetonitrile(EGCG) or methanol (tannic acid) solutions at various drug to EGCG ortannic acid ratios. PBS (EGCG) or water (tannic acid) was added and thefinal solution filtered through a 0.22 micron filter to removeparticulates. The solution was then analyzed for drug concentrationusing absorbance spectroscopy at 450 nm.

EGCG solubilised curcumin up to maximum concentrations of 200 mg per mlEGCG with curcumin at approximately 4700 microgram/ml. The solutionswere stable for 24 hours (FIG. 2A). Tannic acid solubilised curcumin upto maximum concentrations of tannic acid at 500 mg/ml EGCG with curcuminat approximately 12000 microgram/ml. All solutions were stable for 24hours but were temperature sensitive with much reduced curcuminsolubilities at 37° C. or 50° C.

As shown in FIG. 2B, while the free solubility of curcumin is less that1 microgram/ml in water, the presence of EGCG or tannic acidsignificantly increases the solubility of this drug.

Example 3. Solubility of Paclitaxel as a Function of EGCG or Tannic AcidConcentration, Effect of Temperature and 24 Hour Stability of Solutions

Paclitaxel and EGCG or tannic acid were dried down from acetonitrile(EGCG) or methanol (tannic acid) solutions at various drug to EGCG ortannic acid ratios. PBS (EGCG) or water (tannic acid) was added and thefinal solution was filtered through a 0.22 micron filter to remove anyparticulates and the solution was analyzed for drug concentration usingHPLC.

EGCG solubilised paclitaxel up to maximum concentrations of 175 mg perml EGCG with paclitaxel at approximately 1000 micrograms/ml. However thesolutions were not stable over 24 hours (FIG. 3A). Tannic acidsolubilised paclitaxel up to maximum concentrations of 500 mg/ml tannicacid with paclitaxel at approximately 4800 microgram/ml. These solutionswere stable for 24 hours (FIG. 3B). There was no effect of temperatureon EGCG or tannic acid solubilization effects (FIGS. 3C and D). As shownin FIG. 3, while the free solubility of paclitaxel is 1 microgram/ml inwater, the presence of EGCG or tannic acid greatly increases thesolubility of this drug.

Example 4. Solubility of Docetaxel as a Function of EGCG or Tannic AcidConcentration, Effect of Temperature and 24 Hour Stability of Solutions

Docetaxel and EGCG or tannic acid were dried down from acetonitrile(EGCG) or methanol (tannic acid) solutions at various drug to EGCG ortannic acid ratios. PBS (EGCG) or water (tannic acid) was added and thefinal solution filtered through a 0.22 micron filter to remove anyparticulates and the solution was analyzed for drug concentration usingHPLC.

EGCG solubilised docetaxel up to maximum concentrations of 200 mg/mlEGCG with docetaxel at approximately 1500 microgram/ml. The solutionswere stable over 24 hours (FIG. 4A). Tannic acid solubilised paclitaxelup to maximum concentrations 500 mg/ml tannic acid with paclitaxel atapproximately 4000 micrograms/ml (FIG. 4B). However at tannic acidconcentrations above 150 mg/ml the solutions were not stable over 24hrs. There was no effect of temperature on the solubilization effectsfor either EGCG or tannic acid (FIGS. 4 C and D.) The free solubility ofdocetaxel is approximately 5-7 micrograms/ml in water. However, thepresence of EGCG or tannic acid significantly increases the solubilityof this drug.

Example 5. Solubility of Various Hydrophobic Agents in SolutionsContaining EGCG

EGCG at 50 mg/ml and drug at approximately 250 micrograms per ml weredissolved in the listed solvent and dried down in a test tube undernitrogen. 1 ml of water was added, followed by vortexing. The solutionswere examined for particulate matter under a microscope. If noparticulates were present, the process was repeated with a higher drugamount. All the tested drugs remained in solution at the listedconcentrations except for nystatin and hesperdin.

TABLE 1 Drug concentrations obtained using EGCG at 50 mg per ml. DrugParticu- Concentration lates Visual Drug Solvent microgram/ml presentappearance curcumin acetoni- 250 no clear trile yellow/orange solutionamphotericin dmfthf 125 no clear camptothecin thf/dmf 50 no clearplumbagin acetoni- 250 no clear trile yellow/orange solutionindomethacin acetonit 250 no clear solution quercetin aceto/thf 250 noclear coloured liquid nystatin aceto/thf 125 very few clear (not fully)solution ginkgolide B aceto 250 no clear solution bilobalide aceto 250no clear solution hesperedin aceto/THF 125 very few almost clearhesperetin aceto 250 no clear solution

Example 6. The Increased Uptake of Paclitaxel into Cells Using LowConcentrations of EGCG

Paclitaxel was incubated with canine kidney (mdck) cells and their drugresistant counterparts (mdck-mdr) alone or in the presence of EGCG atlow concentrations (10 to 100 ug/ml). In these experiments, paclitaxelwas found to diffuse into mdck cells to achieve levels of approximately200 pg/mg cellular protein and less than this for mdck-mdr (due to drugefflux by the drug resistant pumps probably p-glycoprotein). However incells co-incubated with paclitaxel and EGCG at 50 microg/ml paclitaxelachieved concentrations as high as 2000 pg/mg in both mdck and mdck-mdrcells.

The 10 fold increase in drug uptake in mdck and mdck-mdr cells points toa close association of paclitaxel with EGCG and a transport-assistedinflux of the drug into the cells. This increased drug uptake is anotherunique feature associated with the combined use of EGCG with hydrophobicdrugs.

Example 7. The Increased Uptake and Transport of Docetaxel ThroughMonolayers of Cells

The canine kidney cells, known as MDCK cells, are a non cancerproliferating cell line from canine kidneys. The MDR derivative of thesecells is a multi-drug resistant version. The cell lines MDCK andMDCK-MDR are routinely used in the field of drug resistance because inthe MDCK cells drugs can accumulate and kill the cells whereas the MDRcells contain drug efflux proteins that efflux the drug so that muchhigher drug doses are needed to maintain intracellular concentrationssufficient to kill these cells. Agents that can increase theintracellular concentration of drugs in MDR cells may be useful inovercoming drug resistance or in allowing drugs to enter tissue areasprotected by efflux proteins (e.g. uptake in the gut or brain).

MDCK cells were seeded at 10000 cells per transwell membrane (Becton andDickenson: 0.3 microns, 1 cm diameter) and grown for one week until acontinuous monolayer was present. Drug at 250 micrograms/ml (doped with³H docetaxel, with carrier (tween, diblock (2000 40-60)PDLLA-mepeg orEGCG), all in hanks buffer, were added to the top well (0.4 ml) with 1.2ml of hanks buffer in the base well. The wells were incubated at 37° C.for two hours. The transwells were then disassembled and the amount ofdrug in the base reservoir (transported through the cells) or in thecells (determined by dissolution of the filter after 3 washes in hanksbuffer) was determined by liquid scintillation counting.

In both cell lines, the amount of docetaxel accumulated in the cells ortransported through the cells was increased when cells were incubatedwith EGCG-docetaxel solutions as compared to tween or diblock copolymermicellar solutions. These results illustrate that EGCG allows forenhanced accumulation of docetaxel in cells (FIG. 5).

Example 8. The Transport of Curcumin Through Caco2 Cells

Caco2 cells are continuous cells of human epithelial colorectaladenocarcinoma cells. They contain drug efflux proteins and may be usedin the same way that MDCK-MDR cells are, i.e. to measure drugaccumulation in cells that have the ability to efflux drugs.

Caco2 cells (ATCC, VA, USA) are proliferating gut epithelial cells usedthroughout the pharmaceutical sciences as a model of oral drugavailability. These cells may be grown in cell culture on membraneswhere they align with an apical external surface (equivalent to the gutlumen) and a basolateral lower surface that is equivalent to the cellside adjacent to the blood capillaries. When an EGCG curcumin solutionwas placed in the upper portion of a transwell containing these cells ona membrane for three hours, large amounts of curcumin either passedthrough or accumulated within the caco2 cells.

Caco2 cells were seeded onto 0.3 um transwell membranes and left to growto confluence for 3 days. A conductivity electrode measured theTranscellular electrical resistance value over the next few days andwhen it had reached 600 mohms (tight junctions established) theexperiment began. A solution of curcumin (250 microgram per ml) in EGCG(25 mg per ml) in Hanks buffer pH 7.4. was added to the top well for 3hours. The bottom reservoir, which contains curcumin that has beentransported through the cells, was collected. The filter containingcurcumin inside cells was washed three times in Hanks buffer and thensolubilised in acetonitrile to release intracellular curcumin. Allsolutions were then analyzed for curcumin content using uv-visabsorbance spectroscopy at 430 nm.

FIG. 6 shows the transport of curcumin through cells in the presence ofEGCG and also when EGCG is replaced by a diblock polymer (40/60PDLLA1330-2000 mepeg. Although the diblock copolymer allowed a smallamount of curcumin to pass through and enter the cells, the EGCGsolution allowed for much higher levels of curcumin uptake and transportthrough the cells (FIG. 6). This example clearly illustrates that EGCGsolutions of hydrophobic drugs may be used to render the drugs orallyavailable.

Example 9. Coating of Catheters with Fast Dissolving, Drug SolubilisingCoatings

Diblock copolymer was manufactured in house. Briefly,methoxypolyethylene glycol (MEPEG molecular weight 2000) (UnionCarbide), was placed in a sealed round bottomed flask along with lacticacid (Sigma Chemicals) and heated under nitrogen in an oil bath to 140°C. for 24 hours. Lactic acid then polymerizes on the hydroxyl chain ofthe MEPEG to form a diblock copolymer. The amounts of lactic acid addedwas determined to give a molecular weight polylactic acid chain ofapproximately 1660 joined to the MEPEG 2000 to give a final molecularweight of 3660. This was checked and established by gel permeationchromatography.

When this diblock copolymer is dissolved with hydrophobic drugs in anorganic solvent such as acetonitrile and dried down then upon additionof water the diblock copolymer may dissolve to form micelles in whichthe drug is found in the micelle core. This allows for thesolubilization of the drug.

30 mg of EGCG, or 10 mg tannic acid or 6 mg of diblock copolymer (40/60PDLLA1330-2000 mepeg) and 300 micrograms of paclitaxel were dissolved in400 ul of ethanol. A balloon catheter was inflated and revolved alongits horizontal axis. The drug/EGCG solution was slowly pipetted onto theballoon using 25 microliters at a time and dried with gentle heat froman electric blowdryer. The catheter was left overnight to dry. Thediblock copolymer was mixed with EGCG at defined ratios to give a finalweight of 30 mg.

The coating was found to be strongly bound to the balloon and did notrub off with glove abrasion. The balloon could be inflated/deflated manytimes with no compromise of adhesion of the coating. When these coatingscontaining 10% drug to carrier were placed in water or 5% dextrose for afew seconds a fine precipitate was observed in the carrier before thecarrier dissolved. These precipitates were analyzed (Nanosizer, Malvem)and found to have a size of 110 nm. If left in PBS the precipitatesaggregated to 2 micrometers in size. However, if moistened in PBS andthen dispersed in water or dextrose they formed nanoparticles having adiameter of approximately 110 nanometers.

Although these precipitates only occurred at higher drug to carrierratios, such drug nanoparticles can offer an optimal form of solid drugdelivery to tissues. This may be especially true on an artery wall sinceuptake into the tissue would be potentially improved as compared to muchlarger sized drug precipitates. In some coatings excipients such aspolyethylene glycol or glycerol or hydroxypropylcellulose were added.These coatings performed in the same way as non excipient coatings forma drug perspective but the coatings were more flexible and may bepreferred for certain applications.

Example 10. The Rate of Paclitaxel Release from EGCG Carrier Coatings onBalloon Catheters

A balloon catheter was inflated and revolved along its horizontal axis.30 mg of EGCG, and 300 microg of paclitaxel were dissolved in 400 ul ofethanol. The drug/EGCG solution was slowly pipetted onto the balloonusing 25 microliters at a time and dried with gentle heat from anelectric blowdryer. The catheter assembly was then left overnight todry. To measure the drug release the catheter was inflated and immersedin 5 ml of PBS-albumin buffer at pH 7.4 for a specific time with mildrevolution to create movement. The catheter was then removed and placedin a new tube containing 5 ml of PBS-Albumin for the second drug releasetime point. One ml of dichloromethane was added to each 5 ml of PBS andthe tube shaken. The contents were allowed to settle and the top liquidaspirated off. The dichloromemethane was allowed to dry and then thesolids were redissolved in 60/40 acetonitrile/water v/v and drugquantitated by HPLC analysis (c18 column, 58/5/37acetonitrile/methanol/water at 1 ml/min flow rate with detection at 232nm)

For zero percentage diblock coploymer (i.e. EGCG alone) all paclitaxelwas released in one minute. For 10 percentage diblock copolymer and 20percentage diblock coploymer the rate of release of paclitaxel wasslightly slower from the catheters but was complete within 2 minutes.The addition of 50% diblock copolymer slowed the release ratedramatically as is seen in FIG. 7.

Example 11. Paclitaxel Uptake into Artery Tissue from a Balloon CatheterCoated with Drug and EGCG

A balloon catheter was coated as in example 10 with 30 mg of EGCG and300 microgram of paclitaxel in 400 microliters of ethanol alsocontaining 10 microliters of ³H paclitaxel. A 2-3 cm strip of fresh rataorta artery was placed over a 200 microliter pipette tip and fed ontothe deflated balloon catheter to mimic the feeding of the balloon intothe blood vessel. The balloon was then inflated and the system was leftfor 2 minutes at 37° C. in a bath of Hanks buffered salt solution(HBSS). The balloon was then deflated and 300 microliters of HBSSpipetted into the artery and the wash out collected in a centrifugetube. This wash step was repeated three times. Because the handler'sgloves were moist and had contacted the balloon (and therefore absorbedsome EGCG/drug) the gloves fingers were washed extensively in 100 ml ofHBSS.

The aorta tissue was placed in 500 microliters of tissue solubilizer andleft at 60° C. for 4 hours to digest. The contents were then placed in ascintillation counter. The deployed catheter balloon was observed afterthe procedure. Some of the balloon had not deployed (the balloon wastight in the aorta and not fully inflated) and traces of the reddishcolored EGCG/drug could be observed in the folds. The rest of thecatheter was observed to be clear of all coating. The catheter balloonwas then inflated in 5 ml of acetonitrile to recover the undissolvedEGCG and measured by scintillation counting. All other fractions (aortawash and gloves wash were also counted. These four fractions (aorta,gloves, catheter residual and aorta wash) accounted for all drug and thetotal scintillation count form everything was taken and 100% of theapplied drug.

More than 50% of the total paclitaxel was found to be associated withthe artery and only 2% washed out of the artery following balloondeployment. (FIG. 8) The other fractions (residual in catheter folds andgloves wash) are not really relevant as they were deemed unavailabledrug since that drug was never exposed to the artery wall. Ignoringthose fractions, then approximately 95% of available paclitaxel wastaken up by the artery and less than 5% washed out from the artery.These results clearly show that EGCG allows for excellent paclitaxeltransfer into arteries following a 2 minute contact time.

Example 12. Effect of Ultrasound on Paclitaxel Uptake into Artery Tissuefrom a Balloon Catheter Coated with Drug and EGCG

30 mg of EGCG, and 300 ug of paclitaxel were dissolved in 400 ul ofethanol also containing 10 ul of ³H paclitaxel. A balloon catheter wasinflated and revolved along its horizontal axis. The drug/EGCG solutionwas slowly pipetted onto the balloon using 25 microliters at a time anddried with gentle heat from an electric blowdryer. A 2-3 cm strip offresh rat aorta artery was placed over a 200 microliter pipette tip andfed onto the deflated balloon catheter to mimic the feeding of theballoon into the blood vessel. The balloon was then inflated and thesystem was sonicated for 2 minutes at 37° C. in Hanks buffered saltsolution (HBSS) (4 MHz, 30 watts/cm2). The balloon was then deflated and300 microl of (HBSS) was pipetted into the artery and the wash outcollected in a centrifuge tube. This wash step was repeated three times.Samples were collected as in the previous example.

More than 50% of the total paclitaxel was found to be associated withthe artery and only 2% washed out of the artery following balloondeployment. (FIG. 9). The other fractions (residual on catheter andgloves wash) are not really relevant as they were deemed unavailabledrug since that drug was never exposed to the artery wall. Ignoringthose fractions, then approximately 95% of available paclitaxel wastaken up by the artery and less than 5% washed out from the artery.These results clearly show that EGCG with ultrasound allows forexcellent paclitaxel transfer into arteries following a 2 minute contacttime.

Example 13. Paclitaxel Uptake into Artery Tissue from a Balloon CatheterCoated with Drug and Diblock Copolymer

A balloon catheter was inflated and revolved along its horizontal axis.The drug/diblock solution was slowly pipetted onto the balloon using 25microliters at a time and dried with gentle heat from an electricblowdryer. The solution contained 6 mg of diblock copolymer (40/60pdlla.mepeg-2000 mol. wt. 3333) and 300 ug of paclitaxel in 400 ul ofethanol also containing 10 ul of ³H paclitaxel. A 2-3 cm strip of freshrat aorta artery was placed over a 200 ul pipette tip and fed onto thedeflated balloon catheter to mimic the feeding of the balloon into theblood vessel. The system was then immersed in Hanks buffered saltsolution (HBSS) at 37° C. for 2 minutes. At this time the balloon andtreated and the paclitaxel uptake determined as in Example 11.

Approximately 10% of the total paclitaxel was found to be associatedwith the artery and less than 2% washed out of the artery followingballoon deployment. (FIG. 10). The gloves wash fraction is not reallyrelevant as it was deemed unavailable drug since that drug was neverexposed to the artery wall. The residual on the catheter was significantand it is not known if that drug represented drug in undeployed balloonfolds or was undissolved coating. The diblock copolymer does offer asuitable coating but use may be limited to thinner layers that dissolvemore quickly.

Example 14. Paclitaxel Uptake into Artery Tissue from a Balloon CatheterCoated with Drug and Tannic Acid

30 tannic acid and 300 ug of paclitaxel were dissolved in 400 ul ofethanol also containing 10 ul of ³H paclitaxel. A balloon catheter wasinflated and revolved along its horizontal axis. The drug/tannic acidsolution was slowly pipetted onto the balloon using 25 microliters at atime and dried with gentle heat from an electric blowdryer. Uptake ofpaclitaxel by a 2-3 cm strip of fresh rat aorta artery was thendetermined using the procedure described in Example 11.

Approximately 40% of the total paclitaxel was found to be associatedwith the artery and less than 1% washed out of the artery followingballoon deployment. (FIG. 11.) The gloves wash fraction is not reallyrelevant as it was deemed unavailable drug since that drug was neverexposed to the artery wall. The residual on the catheter wasapproximately 29% and it is not known if that drug represented drug inundeployed balloon folds or was undissolved coating. The amount in thetissue represents the largest fraction of the drug. If we ignore thedrug on the catheter and on the gloves then this amount represents over95% of the available drug transferred to the tissues clearly showingthat tannic acid represents an excellent vehicle for docetaxel deliveryfrom catheters to the blood vessel.

Example 15. Accumulation of Docetaxel in HUVEC Cells and Effect ofUltrasound

Human umbilical vein endothelial cells (HUVEC) and the associatedculture media were obtained from Lonza Chemicals (Basel, Switzerland).All cells were applied to 48 well plates in respective media at aconcentration of 5000 cells per well or filter. The cells were allowedto equilibrate for 3 days at which time they became approximately 80%confluent. In the 48 well plates, only 24 wells were used per plate sothat wells with cells appeared in a checkerboard pattern.

After 2 days, cells were ready for drug incubation with or withoutultrasound treatment. The drug solutions (including radiolabelleddocetaxel) were applied to the cells (0.5 ml) for 2 hours. Some cellswere then ultrasonicated. Briefly, cells received a single 10-s burst ofultrasound at 4 MHz with a power density of 30 W/cm².

After ultrasound treatment, the drug solution was immediately removedand all cells were washed three times with 500 ul of HBSS. The amount ofdocetaxel retained in the cells was determined by lysing the cells in200 ul of lysis buffer (2% Triton X100 containing 33% DMSO) andquantitation by liquid scintillation counting.

The uptake of docetaxel into huvec cells from ECGC formulations wasapproximately 4 fold higher than form the micellar formulation of thedrug (FIG. 12). The application of ultrasound increased the uptake ofdrug into cells from all formulations.

Example 16. Uptake and Transfer of Amphoterecin B into Caco2 Cells UsingEGCG, Tannic Acid or Ambisome Formulations

Caco2 cells were seeded onto 0.3 um transwell membranes and treated asin Example 9. A solution of amphoterecin B (250 ug per ml) in EGCG (25mg per ml), tannic acid (25 mg/ml) in Hanks buffer pH 7.4. or ambisomewas added to the top well for 3 hours. The bottom reservoir wascollected and treated as in Example 8. All solutions were then analyzedfor amphotericin content using uv-vis absorbance spectroscopy at 407 nm.

Although the ambisome formulation of amphotericin allowed a small amountof drug to pass through and enter the cells, the EGCG and tannic acidsolutions allowed for much higher levels of drug uptake and transportthrough the cells (FIG. 13).

Example 17. Manufacture of PAMAM Dendrimer-Crosslinked Gallic AcidCompounds

Protocol for two-step coupling of gallic acid to Go dendrimer using EDCand Sulfo-NHS.

Introduction: TheGo PAMAM dendrimer (Dendritech Midland Mich.) has fourarms each with an amine group on the end terminus. This molecule(molecular weight 517) may be linked to the carboxylate on 4 gallatemolecules using the carbodiimide molecule (EDC) (ethyl dimethylaminopropyl carbodiimide Sigma chemicals USA) in aqueous media.

Materials

A. Activation buffer: water adjust to pH 6

C. gallic acid 440 mg (Sigma chemicals)

D. Sulfo-NHS (Product No. 24510. Thermo fisher)

E. EDC (Sigma chemicals)

F. dendrimer GO. (Dendritech) 1 ml at 2 g/16 ml=125 mg

Method

573 mg EDC (˜1.5M) and 868 mg of sulfo-NHS (˜2M) was added to 2 ml ofwater at pH 5-6 with 440 mg of gallic acid (1.3M in 15% ETOH todissolve) and reacted for 30 minutes at room temperature at pH 4-7. Thisdepended on keeping the gallic acid in solution with stirring. If thereagent did not go into solution, additional water was added.

1 ml of GO dendrimer (120 mM in 1 ml or 40 mM in 3 ml) was added and thepH was adjusted to between 7 and 8.5. Reacted for 2 hours. The reactionmixture was placed in a dialysis bag at about 500 cut off overnight toyield the final product. The reaction scheme is shown in FIG. 14.

Example 18. Drug in EGCG or Tannic Acid Films, Effect of PEG or Glycerol

Thin films of drugs were cast in either EGCG or tannic acid from ethanolsolutions. Drugs in either EGCG or tannic acid were dissolved in ethanolat a final total concentration of 20% w/v and spot pipetted in repeated10 microliter volumes and allowed to dry between spotting. This alloweda thin film to accumulate and dry. Some solutions contained eitherglycerol or polyethylene glycol 300 at 10% or 20% w/w to EGCG or tannicacid. The films were allowed to dry and examined by optical microscopyfor drug precipitation. Films were allow analyzed by differentialscanning calorimetry (DSC) for identify drug crystals.

Curcumin precipitated out at approximately 5% w/w. However, paclitaxeland docetaxel remained dispersed at the molecular level up to 90% drugloadings. The presence of paclitaxel crystals was confirmed at 90% drugloadings by DSC. Rapamycin remained in solution at 50% or more drug:EGCGor tannic acid levels. (FIG. 15) The addition of PEG 300 or glycerol at10% had no significant effect on these values. However, films wereslightly more flexible following the addition of these agents at 10 to20% w/w/ to EGCG or tannic acid.

These data were unexpected since paclitaxel precipitates out ofpolymeric films at approximately 5% loadings. The high levels ofmolecular level drug in EGCG or tannic acid films offers a way ofmaintaining drugs like paclitaxel, docetaxel or rapamycin in a tissueavailable form (molecular rather than particulate) in film coatings ofdevices.

Example 19. Electrospun EGCG/Drug Complexes in Hydrophobic Polymer

Polylactic co glycolic acid was dissolved in 75:25tetrahydrofuan:dimethly formamide at 20% w/v. EGCG or tannic acid at 30%to the PLGA solution along with paclitaxel or curcumin at 2% w/w to EGCGor tannic acid. The solution was electrospun at 20000 volts ontoaluminium foil. After three hours a fine matt of nanofibers had beenspun. Under microscope inspection the meshes appeared homogenous innature.

Example 20. Solubility of Rapamycin as a Function of EGCG or Tannic AcidConcentration, Effect of Temperature, pH and Stability at 24 Hours

Rapamycin and EGCG or tannic acid were dried down from acetonitrile (ormethanol for tannic acid) solutions at various drug to EGCG or tannicacid ratios. PBS (EGCG) or water (Tannic acid) was added and the finalsolution was filtered through a 0.22 um filter to remove anyparticulates and the solution was analyzed for drug concentration usingHPLC.

EGCG solubilized rapamycin up to maximum concentrations of 200 mg per mlEGCG with amphotericin at approximately 300 microgram/ml. Solutions werestable for 24 hours (FIG. 16(a)). There was little effect of temperatureon solubility levels Tannic acid solubilised rapamycin up to maximumconcentrations of 500 mg per ml Tannic acid with amphotericin at approx.1500 ug/ml. Solutions were stable for 24 hours (FIG. 16(b). There was noeffect of temperature on solubility levels

As shown in FIG. 16, while the free solubility of rapamycin isapproximately 2-3 ug/ml in water, the presence of EGCG or tannic acid isable to massively increase the solubility of this drug.

Example 21. Rapamycin Uptake into Artery Tissue from a Balloon CatheterCoated with Drug and EGCG

The balloon catheter was coated with 30 mg of ECGC and 300 microg ofrapamycin in 400 ul of ethanol. A 2-3 cm strip of fresh rat aorta arterywas placed over a 200 ul pipette tip and fed onto the deflated ballooncatheter to mimic the feeding of the balloon into the blood vessel. Theballoon was then inflated and the system was left for 2 minutes at 37°C. in a bath of hanks buffered salt solution (HBSS). At that time theballoon was deflated and 300 microliters of HBSS was pipetted into theartery and the wash out collected in a centrifuge tube. This wash stepwas repeated three times. Because the handler's gloves were moist andhad contacted the balloon (and therefore absorbed some EGCG/drug) thegloves fingers were washed extensively in 100 ml of HBSS. The aortatissue was placed in 500 ul of ethanol and cut up with fine scissors andthen homogenized (polytron at mark 3 for 30 seconds). The deployedcatheter balloon was observed after the procedure. Some of the balloonhad not deployed (the balloon was tight in the aorta and not fullyinflated) and traces of the reddish colored EGCG/drug could be observedin the folds. The rest of the catheter was observed to be clear of allcoating. The catheter balloon was then inflated in 5 ml of acetonitrileto recover the undissolved egcg and drug measured by HPLC. All otherfractions (aorta wash and gloves wash) and catheter extracts wereanalyzed by HPLC. These four fractions (aorta, gloves, catheter residualand aorta wash) accounted for all drug and the total HPLC drug amountwas taken and 100% of the applied drug.

Results: More than 50% of the total paclitaxel was found to beassociated with the artery and less than 2% washed out of the arteryfollowing balloon deployment. (FIG. 17) The other fractions (residual incatheter folds and gloves wash) are not really relevant as they weredeemed unavailable drug since that drug was never exposed to the arterywall. If we ignore those fractions, then more than 95% of availablepaclitaxel was taken up by the artery and less than 5% washed out fromthe artery. These results clearly show that EGCG allows for excellentrapamycin transfer into arteries following a 2 minute contact time.

Example 22. Finasteride Solubilization in ECGC or Tannic Acid andMeasurement the Encapsulation and Release of Finasteride from PVA andEmbospheres Following Incubation in EGCG or Tannic Acid Solution ofFinasteride

The solubilization effect of EGCG or tannic acid on finasteride.

Method: Solutions of finasteride and either EGCG or tannic acid atvarious weight percentages in ethanol were dried down under nitrogen.Water was added and the dried material suspended/dissolved. The contentswere then centrifuged at 3000×G and filter through a glass filter (1 um)and finasteride solubility determined by HPLC. The pH of tannic acidsolutions was brought up to 7 by the addition of NAOH. EGCG has littleeffect on pH (drops to pH 6 at 200 ug/ml) so these solutions were notadjusted.

Results: EGCG increased the solubility of finasteride in a concentrationdependent manner. At 150 mg/ml EGCG the solubility of finasteride waselevated from 75 ug/ml to over 10 mg/ml at either 25° C. or 37° C. andsolutions were stable over 24 hours at 25° C. A similar effect wasobserved for tannic acid which allowed for a finasteride solubility of8-10 mg/ml using tannic acid at 200 mg/ml.

Method: PVA foam embolization particles (Cook. Medical Bloomington Ind.)size 180-300 um. Vial of 220 mg split into two. 150 mg of EGCG with 10mg of finasteride or 250 mg tannic acid with 1 mg of finasteride weredried as a common film from ethanol and solubilised in 1 ml of water andadded to the 100 mg of PVA particles. Solutions were mixed for 30minutes. At this time it was observed that all the EGCG or tannic acidcolor (pink or brown respectively) had disappeared from the solution andgone into the PVA which was now heavily colored. The solution wasdiscarded and the PVA freeze dried. 10 mg of the EGCG formulation or 5mg of the tannic acid formulation was added to 2 ml of PBS (pH 7.4) andthe release of finasteride was measured over 2 weeks.

Embospheres: Syringe contents ((Embospheres 500-700 um Merit Medical S.Jordan UT) were split into two and incubated in water solutions offinasteride (1 mg/ml in 35 mg of EGCG or tannic acid made up from driedfilms as above) for 30 minutes with shaking. At this time it wasobserved that all the EGCG or tannic acid color (pink or brownrespectively) had disappeared from the solution and gone into theEmbospheres which were no heavily colored. The solution was discarded.20% of the resulting particles (still wet) were then placed inmicrocentrifuge tubes containing 2 ml of PBS and drug release wasmeasured.

Results: All formulations released the drug in a controlled manner. Thefastest release observed was for PVA incubated with tannicacid/finasteride solutions (100% release in 3 days) whilst the otherembolic particles released the drug over a two week period. (FIG. 18)

Example 23. Release of Finasteride from PLGA Microspheres+/−Egcg orTannic Acid

Encapsulation pf paclitaxel and tannic acid or EGCG in PLGA microspheresof approximately 200 micrometers diameter.

Method: The method involved pipetting a solution of the polymer PLGA(usually 20% w/v) and drug (usually 5% w/w to polymer) and EGCG (e.g.20% w/w/ to polymer) in dichlomethane (DCM) (5 ml) into 100 ml of 2.5%PVA solution in water stirring at 450 rpm. The suspension was leftstirring for 2 hours and the microspheres washed 4 times in distilledwater. The microspheres were then dried under vacuum for 2 days. Drugencapsulation was measured by dissolving a known weight of microspheresin 1 ml of dichloromethane followed by immediate dilution to 10 ml in60:40 acetonitrile/water. The amount of drug or EGCG in the top andbottom phase of this solution was measured using HPLC methods (mobilephase 58:37:5 Acetonitrile:water:methanol. 1 ml per min flow on a c18column with detection at 232 nm)

Results: Both EGCG and paclitaxel were encapsulated at high efficiency(greater than 50% efficiency) in PLGA microspheres. Yields ofmicrospheres were good (greater than 50%). Microspheres wereapproximately 200 micron in diameter and there was clear evidence ofEGCG in the spheres which appeared pink in color (color of EGCG) andunder optical microscopy, small particles of EGCG could be seen with thePLGA microspheres.

Tannic acid: An alternative method was used, termed a water-in oil-inwater emulsion. This method involved pre-dissolving the tannic acid in asmall volume (typically 200 micrometers) of 0.05% Span 80 in water andadding this immiscible water phase to the PLGA/paclitaxel/DCM phase withtip sonication. This forms a primary emulsion of water droplets in thePLGA solution stabilized by Span. When this emulsion was pipetted intothe PVA solution the microspheres formed well. Using this methodmicrospheres (200 micrometers) were obtained at high yields (greaterthan 50%) with high loadings of both paclitaxel and tannic acid (greaterthan 50%). The microspheres were a light brown in color indicative oftannic acid encapsulation.

Methods: In these studies, 10 mg of microspheres were suspended in 2 mlof phosphate buffered saline (pH 7.4 10 mM phosphate) in microcentrifugetubes and tumbled at 8 rpm at 37° C. The tubes were then centrifuged at12000×g and the supernatants collected for drug analysis by HPLC. 2 mlof fresh PBS was then placed on top of the microspheres which werereturned to the 37° C. oven for continued incubation with tumbling.

Finasteride: The release rate of finasteride from the PLGA microspheresis shown in FIG. 19. Finasteride released very slowly from the PLGA ifno EGCG or Tannic acid was included in the formulation so that only 7%of encapsulated drug had released after 32 days. However the addition ofeither EGCG or Tannic acid to the microspheres greatly enhanced drugrelease rates so that for both systems a steady release rate offinasteride was obtained over the first 20 days (approx 80% of drugreleased) followed by a slower steady release over the next 20 days.After approx 40 days the release rate increased again until themicrospheres had completely broken up and degraded by day 50.

At the end of the study the residual mass of polymer and drug wasdissolved in DCM and drug extracted into 60:40 acetonitrile:water tomeasure residual drug. The amounts of residual drug were 89% for plgaalone (at 31 days), 16% for EGCG and 8% for tannic acid (both at 51days) as expressed as a % of the original loading. These resultsapproximately match the release profiles in that almost all the drugremained in the PLGA alone spheres and only a small amount of drugremained in the polymer for the EGCG and Tannic acid formulations.

EGCG or Tannic acid: The release of EGCG or Tannic acid from PLGAmicrospheres was also measured. Both EGCG and Tannic acid releasedsteadily over a 10 days period to levels of approximately 45% and 65%respectively. After that time the release rate was very slow and was nondetectable by day 31.

These profiles establish the excellent qualities of PLGA microspherescontaining EGCG or Tannic acid as controlled release formulations offinasteride. The continued release of EGCG or Tannic acid over 30 daysalso allows some controlled release of these compounds.

Example 24. Solubility of Finasteride as a Function of EGCG or TannicAcid Concentration; Effect of Temperature and 24 Hour Stability ofSolutions

Method: drug and EGCG or tannic acid were dried down from acetonitrile(or methanol for tannic acid) solutions at various drug to EGCG ortannic acid ratios. PBS (EGCG) or water (Tannic acid pH adjusted to 7)was added and the final solution was filtered through a 0.22 um filterto remove any particulates and the solution was analyzed for drugconcentration using HPLC methods.

Results: EGCG solubilised finasteride up to maximum concentrations of150 mg per ml EGCG with drug at approx. 11000 microg/ml and solutionswere stable for 24 hours (FIG. 20). Tannic acid solubilised finasterideup to maximum concentrations of tannic acid at 200 mg/ml EGCG with drugat approximately 10000 microgram/ml (FIG. 21). All solutions were stablefor 24 hours and were temperature insensitive.

Example 25. The Uptake of Docetaxel or Paclitaxel into Pig BladderTissue Using Solutions with EGCG or Tannic Acid as Carriers

Methods: Fresh ex vivo pig bladders were cut into 2 cm diameter piecesand laid on franz diffusions cells. Tritium labeled docetaxel orpaclitaxel solutions were manufactured by dissolving EGCG or tannic acidand drug along with a small volume of tritium labelled drug (Moravek CA,1 microCi/microl) in ethanol and drying down. Alternatively, docetaxelor paclitaxel was made up to the same drug solution strength by dilutionof the commercial formulations of the drug (tween 80 for docetaxel andcremophor for paclitaxel). The solutions were then made up in tyrodesbuffer pH 7.4 and 400 ul was placed on the urothelial side of the tissuefor 2 hours. The tissues were then frozen and cryosectioned forradioactivity counting by liquid scintillation methods.

Results: Experiment 1: Using docetaxel or paclitaxel at 200 microg/ml ineither EGCG or tannic acid at 50 mg/ml allowed for high levels of drugpenetration through bladder tissue as shown in FIGS. 22 A and 22 Brespectively. The levels of drug penetration far exceeded those achievedusing either tween or cremophor formulations of the drugs.

Using EGCG or tannic acid as drug carriers allows for high levels ofdrug penetration into the bladder tissues.

Example 26. The Uptake of Paclitaxel into Pig Bladder Tissue Using EGCGor Tannic Acid in Methoxypolyethylene Glycol Pastes

Methods: Fresh ex vivo pig bladders were cut into 2 cm diameter piecesand laid on franz diffusions cells. Tritium labeled paclitaxel loadedpolymeric pastes were manufactured containing 57% methoxypolyethyleneglycol (MEPEG 350, Union Carbide), 38% tannic acid or egcg and 5% byweight drug with 10 ul of 3H (tritium) labelled drug (1 uCi/ul) bydissolution in a small volume of ethanol and dried with blending. 100 mgof paste was applied to either the perivascular or urothelial side ofthe bladder tissue and 200 ul of tyrodes buffer pH 7.4 was added. Thetissue was incubated for 2 hours at 37° C. and then the diffusion cellwas disassembled, the tissue was washed free of remaining paste withexcess tyrodes and the tissues were then frozen and cryosectioned forradioactivity counting by liquid scintillation methods.

Results: Both EGCG and tannic acid loaded formulations allowed for thepenetration of paclitaxel into the bladder tissue when applied on eitherthe urothelail or perivascular sides of the bladder wall as shown inFIG. 23. The data is shown as distance from the respective appliedsurface so that urothelail data reflects the tissue depth profile fromthe urothelial surface through to the outer fatty layer (perivesicularsurface) and the perivesicular data runs in the reverse direction

Example 27. The Uptake of Paclitaxel or Docetaxel into Pigs BladderTissue Using EGCG or Tannic Acid in a Triblock Copolymer or a DiblockCopolymer-Methoxypolyethylene Glycol Paste Application to thePerivesicular Surface

Methods: Fresh ex vivo pigs bladders were cut into 2 cm diameter piecesand laid on franz diffusions cells. Tritium labeled paclitaxel ordocetaxel loaded polymeric pastes were manufactured containing 45%methoxypolyethylene glycol (MEPEG 350, Union Carbide), 30% triblockcopolymer or diblock copolymer with either tannic acid or egcg at 25%and 5% by weight drug with 10 microl of ³H (tritium) labelled drug (1microCi/microl) by dissolution in a small volume of ethanol and driedwith blending. The synthesis of the diblock copolymer is described inexample X and is composed of a MEPEG molecule of 2000 molecular weightwith polylactic acid at a molecular weight of 1330. The triblockcopolymer was synthesized in house and has a composition of 35/35/30(polycaprolactone, polylactic acid, polyethylene glycol with a totalmolecular weight of 4600. The triblock was synthesized by heating amixture of caprolactone (Sigma chemicals) lactic acid (Polysciences) andPolyethylene glycol (Sigma molecular weight 1380) to 120° C. undernitrogen overnight followed by cooling and washing in hexane or coldethanol. 100 mg of paste was applied to the perivascular side of thebladder tissue and 200 ul of tyrodes buffer pH 7.4 was added. The tissuewas incubated for 2 hours at 37° C. and then the diffusion cell wasdisassembled, the tissue was washed free of remaining paste with excesstyrodes and the tissues were then frozen and cryosectioned forradioactivity counting by liquid scintillation methods.

Results: Both EGCG and tannic acid loaded triblock copolymerformulations allowed for the penetration of both paclitaxel anddocetaxel into the bladder tissue when applied on perivesicualr sides ofthe bladder wall. The data is shown in FIG. 24 as distance from theapplied surface to the urothelial side. Both EGCG and Tannic acid loadeddiblock copolymer pastes allowed for the penetration of paclitaxel intothe bladder wall when applied onto the perivesicular side of the bladderwall as shown in FIG. 25.

Example 28. Methods and Formulations for Dermal Drug Delivery

Various gallate-containing drug formulations were prepared and appliedto ex vivo pig skin samples. Fresh pig skin was obtained from a localbutcher, processed within three hours and then frozen. For experiments,the skin was slowly thawed, excess fat removed from the base, and cutinto 1×2 cm squares. These squares were mounted and clamped on Franzdiffusion cells, which kept the tissue moist and isolated and exposed a6 mm diameter of the upper skin surface for the application of a drugloaded formulation. Skin samples were then frozen and latercryosectioned in 50 μm slices. The drug in the slices was extracted andmeasured by HPLC or radioactive doping methods. A drug depth profile wasthen established for each drug. In all cases, high levels of drugpenetration were found for gallate-containing drug formulations. Theselevels were higher than levels for non-gallate containing commercialcontrol formulations.

Formulations were prepared based on seven drugs (paclitaxel, docetaxel,curcumin, retinoic acid, lidocaine, amphotericin B, and finasteride), asfollows:

1. Formulations containing a drug and a gallate. The drugs weredissolved in ethanol at various concentrations along with either EGCG orTA (500 mg/mL). Each solution was pipetted into 6×5 mm diameter aluminumcups (approximately 3 mm in height) by filling and allowing the ethanolto evaporate at 50° C. until all the solution was used up (80 mg percup).

2. Formulations containing a drug, propylene glycol (“PG”) and agallate. 300 mg of propylene glycol was mixed with 200 mg of EGCG or TAuntil dissolved. Various amounts of drug were added to this mixture anddissolved. 80 mg of the resulting viscous solution was weighed into 6×5mm aluminum cups.

3. Control Formulations. Control formulations were prepared using Glaxalbase and Plogel. Glaxal base is a cream used by compounding pharmaciststo manufacture topical formulations of drugs. Plogel is an alternativeused for dermal formulations. Plogel formulations were supplemented withlabrasol (50%), which is a penetration enhancer. Drug was added to aknown weight of Glaxal or Plogel and levigated to produce a standarddrug dispersion. These formulations were prepared the evening before theexperiment. For some drugs, radioactive drug (where available) was alsoadded as a doping additive to facilitate quantitation in tissues.

Eutectics: In some cases, gallate containing compounds and drugs wereformulated in eutectic mixtures. These included a 60:40 (% w/w) mixtureof menthol with ibuprofen. These agents acted as a carrier for retinoicacid, which was then dissolved in this liquid. The 3-drugeutectic/solution was then blended into the CMC/poloxamer emulsioncontaining EGCG (2.5%). Another eutectic system used a 50:50 (% w/w)mixture of lidocaine with menthol blended into a carboxymethyl cellulosegel containing 2.5% w/w EGCG. The emulsion was stabilized withpoloxamer.

Example 29. Pig Skin Studies

Aluminum cups containing drug formulations were inverted on top of thepig skin in the Franz diffusion cell so that the formulation contentswere in contact with the skin. 80 mg of Glaxal/drug or Plogel/drugmixture were added to control skin surfaces. 50 μL of Tyrode'sphysiological buffer at pH 7.4 was added to the top chamber with theformulation and the base of the cell was also filled with the samebuffer solution.

The top chambers were capped (to keep the skin surface moist) and thecells were incubated in the dark at 37° C. in a humid incubator for sixhours. The cells were then dismantled sequentially and the 6 mm centerpiece of the skin was excised with scissors and flash frozen (liquidnitrogen) with the skin surface flat on a metal plate. The samples werethen stored at −80° C. until use. Six skin samples were prepared performulation.

For most qualitative experiments, the paste consisted of 60% PG with 40%EGCG or TA. Various amounts of drug were suspended into these pastes tostudy drug dissolution. For lidocaine, pastes were made using 50:50(PG:gallate), 60:40, 70:30 or 80:20 (% w/w) and contained 5, 10, 15 or20% of lidocaine (w/wl to paste) fully dissolved in these pastes.

Analysis. Frozen skin sections were mounted in a cryotome with the flatskin surface facing the cutting blade. For all drugs, the samples werethen cut in 50 μm thick pieces and pooled into groups of sections fordrug extraction. Skin samples were then weighed and soaked in 300 μL ofacetonitrile to extract drugs (for amphotericin B a 50:50 mixture ofmethanol and acetonitrile was used). The amount of drug in each group ofskin sections was then determined using HPLC methods, or byradioactivity counting on a liquid scintillation counter. The amount ofdrug in each group of skin sections was expressed as pg/g or mg/g oftissue.

Example 30

Results: Drug penetration into pig skin.

1. Paclitaxel—FIG. 26 shows the uptake of paclitaxel by pig skin aftersix hours of incubation using different formulations containingpaclitaxel (ptx) at 0.6% w/w. The zero mark on the x-axis represents theskin surface origin (0), and deeper cuts go to the right on the x axis.

As shown in FIG. 26, the control formulations (Glaxal and Plogel,without a gallate compound) exhibited low levels of drug uptake.Formulations with EGCG and paclitaxel alone exhibited high levels ofdrug uptake (˜1000 μg/g). Formulations with EGCG-Propylene glycol (PG)paste exhibited even higher levels (almost 5000 μg/g) of uptake.Formulations with tannic acid and paclitaxel alone, or with tannic acidin PG exhibited higher levels of uptake as compared to the controlformulations (bar 5 on each graph), but lower than the EGCG basedformulations (bar 4 on each graph). The data illustrates that EGCG-basedformulations give some level of drug in the mid dermis layer (250-500μm).

FIG. 26 also illustrates results for an emulsion formed by dissolvingpaclitaxel in a eutectic solution of 50:50 lidocaine and menthol (%w/w). In a first step, 5.5% of paclitaxel was dissolved in the eutectic.Then, in a second step the eutectic of paclitaxel was blended into anemulsion of carboxymethyl cellulose stabilized with poloxamer that alsocontained EGCG (final paclitaxel concentration was 0.6%). As seen inFIG. 26, the emulsion provided increased uptake of paclitaxel ascompared to the control formulations, but less than the other EGCG ortannic based formulations.

2. Docetaxel—FIG. 27 shows the uptake of docetaxel by pig skin after sixhours of incubation using different formulations containing docetaxel at0.6% w/w. The zero mark on the x-axis represents the skin surface origin(0), and deeper cuts go to the right on the x axis.

As shown in FIG. 27, the general order and intensity of drug uptakebetween the formulations is similar to those seen with paclitaxel.Formulations with EGCG and docetaxel alone exhibited high levels of druguptake (over 400 μg/g). Formulations with EGCG-Propylene glycol (PG)paste exhibited even higher levels (over 1300 μg/g) of uptake.Formulations with tannic acid and docetaxel alone, or with tannic acidin PG exhibited higher levels of uptake as compared to the controlformulations, but lower than the EGCG based formulations. Highest druguptake was achieved using EGCG in a paste. In general, the uptake levelswere higher for paclitaxel than for docetaxel.

There is a rule of thumb in the topical drug delivery field called the“500 Dalton rule.” This rule predicts that only agents with a molecularweight smaller than 500 Dalton can penetrate the skin. The EGCGmolecules have a molecular weight of 450 Da, and can pass through theskin. Paclitaxel and docetaxel, on the other hand, have molecularweights close to 900 Da and, based on the 500 Dalton rule, should notpenetrate the skin. However, each of these drugs exhibited skinpenetration when combined with EGCG or tannic acid.

3. Lidocaine—FIG. 28 shows the uptake of lidocaine by pig skin after asix hour incubation using different formulations containing lidocaine at4% w/w. The zero mark on the x-axis represents the skin surface origin(0), and deeper cuts go to the right on the x axis.

Lidocaine was taken up from each of the formulations, with levels oflidocaine persisting into the 250-500 μm deep mid-dermal layer. However,the EGCG, PG/EGCG, and PG/tannic acid formulations each exhibited higherlevels of uptake in the 0-250 μm layer compared to the controlformulations, with PG/EGCG exhibiting over 3 times higher uptakecompared to the control formulations, and PG/tannic acid exhibitingnearly 4-5 times higher uptake compared to the control formulations.

FIG. 28 also illustrates results for a eutectic. This eutecticformulation of lidocaine showed higher uptake levels in the 0-250 μmlayer than the two control formulations in Glaxal base and Plogel.

FIG. 29 shows the rate of uptake of lidocaine from PG:EGCG pastecompared to lidocaine from a EMLAcommercial cream. EMLA is an acronymfor “Eutectic mixture of liquid anesthetics.” EMLA is an anestheticcream comprising 5% drug, a eutectic mixture (two solids together form aliquid with a lower melting point than either of the solids alone) ofprilocaine and lidocaine in a cream emulsion.

Franz diffusion cells were set up as described previously, butincubation times were shorter at 10, 20, 30, 45, or 60 minutes. Skinsections of 25 μm were cut using acryostat in two groups of 10 to yield0-250 μm depths and 250-500 μm depths respectively. Prilocaine andlidocaine were separated and quantified using an appropriate HPLCmethod.

As shown in FIG. 29, preliminary results indicate that EMLA and EGCGexhibit similar penetration rates over the first 20 minutes. However,EGCG exhibited similar or greater penetration than EMLA thereafter, at30, 45 and 60 minutes, respectively.

4. Retinoic acid—FIG. 30 shows the uptake of retinoic acid by pig skinafter a six hour incubation using different formulations containingretinoic acid at 0.6% w/w. The zero mark on the x-axis represents theskin surface origin (0), and deeper cuts go to the right on the x axis.

As shown in FIG. 30, retinoic acid was taken up from each of theformulations, with EGCG, PG/EGCG, and PG/tannic acid formulationsexhibiting higher uptake than the control formulations. Formulationswith EGCG and retinoic acid alone exhibited high levels of drug uptake(˜1400 μg/g). Formulations with EGCG-Propylene glycol (PG) pasteexhibited even higher levels (˜1900 μg/g) of uptake. In the 0-250 μmdepth samples, formulations with tannic acid in PG exhibited higherlevels of uptake as compared to the control formulations, but lower thanthe EGCG based formulations.

FIG. 30 also illustrates results for a eutectic. This eutectic exhibitedsimilar or higher levels of drug uptake when compared to controlformulations.

5. Amphotericin B—FIG. 31 shows the uptake of amphotericin B by pig skinafter a six hour incubation using different formulations containingamphotericin B at 0.6% w/w. The zero mark on the x-axis represents theskin surface origin (0), and deeper cuts go to the right on the x axis.

As shown in FIG. 31, EGCG and tannic acid based formulations ofamphotericin B each exhibited higher drug uptake levels than either ofthe Plogel and Glaxal control formulations, with these controlformulations exhibiting little to no uptake. Formulations with EGCG ortannic acid alone exhibited high levels of drug uptake (over 600 μg/gand ˜300 μg/g, respectively). Formulations with EGCG-Propylene glycol(PG) or tannic acid-Propylene glycol paste exhibited somewhat lowerlevels of drug uptake (˜400 μg/g and ˜300 μg/g, respectively), but stillsignificantly greater uptake than the control formulations. Although thenon-PG containing formulations gave the highest level of uptake, the PGpastes nonetheless provide strong uptake compared to unsupplementedGlaxal Base and Plogel. For the mid-dermal regions (250-500 μm), thecontrol formulations exhibited no drug penetration.

6. Curcumin—FIG. 32 shows the uptake of curcumin by pig skin after a sixhour incubation using different formulations containing curcumin at 0.6%w/w. The zero mark on the x-axis represents the skin surface origin (0),and deeper cuts go to the right on the x axis.

As shown in FIG. 32, Glaxal base and Plogel control formulations ofcurcumin exhibited essentially no drug uptake. EGCG and tannic acidbased formulations, on the other hand, exhibited high uptake of the drug(EGCG (over 1600 μg/g); tannic acid (over 700 μg/g); EGCG/PG (˜4000μg/g); tannic acid/PG (˜1400 μg/g). In general, ECGC based formulationsprovided higher uptake than tannic acid formulations, with PG/gallateformulations exhibiting higher uptake than the respective non-PGformulations.

7. Finasteride—FIG. 33 shows the uptake of Finasteride by pig skin after6 hour incubation using different formulations containing finasteride at0.25% w/w. The zero mark on the x-axis represents the skin surfaceorigin (0), and deeper cuts go to the right on the x axis.

As shown in FIG. 33, the Glaxal base control paste exhibited low druguptake. EGCG and tannic acid based formulations, on the other hand,exhibited high levels of drug uptake (EGCG (over 500 μg/g); tannic acid(over 250 μg/g); EGCG/PG (over 1200 μg/g); tannic acid/PG (over 600μg/g). EGCG based formulations generally exhibited higher uptake levelsthan tannic acid based formulations. PG/gallate formulations were moreeffective than gallate drug formulations, again demonstrating theincreased efficacy of gallate formulations as pastes.

Example 31. Injectable Gallate-Based Pastes

EGCG and tannic acid are fairly soluble in alcohol and acetonitrile. Itwas found that these agents were very soluble in propylene glycol andpolyethylene glycol 300. Solubilities higher than 50% w/w wereachievable for propylene glycol and 25% gallate:75% PEG using PEG 300.These solutions become more viscous and paste-like as the percentage ofgallate in solution is increased. When non-drug containing pastes wereplaced in water, the contents of the paste (gallate, PG or PEG), whichare all water soluble, dissolved away.

For injection, a paste composed of 50:50 w/w/, PG:gallate gives a ratherviscous paste but at 60:40 and higher (PG) the paste is injectablethrough 21 gauge needles.

Methods: 60:40% w/w PG:EGCG or PG:tannic acid was used in these studies.588 mg of propylene glycol was weighed into a 20 mL glass vials and 392of EGCG or tannic acid was added followed by vortexing to distribute anddissolve the gallates. The vials were warmed to 60° C. and vortexeduntil all the contents were in solution. At this time 20 mg of drug wasadded (2% w/w) and vortexed until in solution. The following drugs wereused: paclitaxel, docetaxel, retinoic acid, amphotericin B, andcurcumin. 100 mg of each paste was weighed into the base of a 15 mLglass test tube and 10 mL of phosphate buffered saline was added at pH7.4 and the tubes were incubated at 37° C. for certain times. All 10 mLof the PBS release media was removed and 1 mL analyzed by HPLC for drugcontent. 10 mL of fresh PBS was then added to all tubes

Results: At 2% drug loading, the paste in all tubes formed a gel-likemass when PBS was added but that mass broke up over 24 hours. Sincethese drugs were all hydrophobic in nature, there was a small solid massleft at 24 hours. FIG. 34 illustrates the results of a drug releasestudy over 24 hours for paclitaxel and docetaxel (1%) from gallatepastes. FIG. 35 illustrates the result of a release study over 24 hoursfor retinoic acid, amphotericin B, and curcumin (1%) from gallatepastes.

The drugs paclitaxel, docetaxel, curcumin, retinoic acid andamphotericin B are potent drugs that normally are formulated atrelatively low concentrations (e.g., 2%). The pastes described in thisexample are viscous, and can be injected into any tissue compartment,for example via catheter lines. These pastes provided relativelycontrolled release of the drug over 24 hours. This is highlyadvantageous over injecting a drug in a liquid solution, where the drugis immediately dispersed within the body and quickly cleared from thetissue. In one example, docetaxel may be injected directly into theprostate to deliver the drug accurately in one small location, as thepaste stays intact for hours.

Example 32. Lidocaine Containing Gallate Paste: PEG300:Gallate Pastes

EGCG and tannic acid were found to be soluble in PEG 300 liquid at 25%w/w. When lidocaine was dissolved in this paste and the paste placed inPBS, there was a partial solidification of the paste, followed by adisintegration/dissolution over 3 days.

Example 33. Lidocaine Containing Gallate Paste:Propylene Glycol:GallatePastes

Surgery is associated with post-operative pain. This may range fromsevere acute pain at 24 hours, to acute pain for days, to subacute painfor many weeks, and may be followed by chronic pain lasting many monthsor up to a year. Pain over the first days or week is typically treatedwith systemically delivered drugs, such as oral analgesics (e.g.,acetaminophen, NSAIDS, and opioids). These treatments have potentialdrawbacks, including the potential for addiction. It would beadvantageous to have an injectable formulation that can be used todeliver an analgesic and/or anesthetic internally for the localtreatment of pain, and preferably a formulation that releases theanalgesic and/or anesthetic in a controlled manner over an extendedperiod of time.

Method: Lidocaine pastes were formulated by dissolving various amountsof lidocaine (5, 10, 15 or 20% w/w) in various combinations of propyleneglycol:EGCG or propylene glycol:tannic acid (60:40, 70:30, or 80:20).For each formulation, 100 mg of paste was placed in the base of a roundbottomed 15 mL glass test tube. When viewed from the top (open tube) thepaste mass had a diameter of approximately 8 mm. At the start of therelease experiment, 10 ml of PBS was added and the tubes left forvarious time periods, after which all 10 mL of the release media wasremoved for drug analysis. The residual mass was observed from the top,and the drop in diameter from 8 mm noted as a semi-quantitative assessedof paste pellet degradation. It was not possible to measure thedegradation fully quantitatively at that time, as the pellets werefragile and water-swollen. After a few days the pellets became lessfragile, and were removed from the tubes and dried on tissue paperbefore weighing. The drop in weight from 100 mg was then noted as the %degradation and compared with the visual observations. In all casesthese values matched to within 5% accuracy.

Results: FIGS. 36A-36C show the release of lidocaine from EGCG:propyleneglycol pastes with various amounts of lidocaine (20%, 15%, 10%, and 5%),and at various ratios of EGCG:propylene glycol. At 5% drug loading, allEGCG pastes exhibited almost 100% drug release in approximately 2 days.Drug release was extended by increasing the drug loading to 10%, 15%,and 20%, respectively. At 20% drug loading, the EGCG pastes releaseddrug over a period of between approximately 2-4 weeks. The order ofrelease was generally affected by the PG % in the paste so that drugrelease was higher as follows: 80% PG>70% PG>60% PG.

FIGS. 37A-37C show the degradation of the various lidocaine pastesreflected in FIGS. 36A-36C. The degradation curve profiles in FIGS.37A-37C generally mirror the release profiles in FIGS. 36A-36C.

FIGS. 38A-38C show the release of lidocaine from tannic acid:propyleneglycol pastes with various amounts of lidocaine (20%, 15%, 10%, and 5%),and at various ratios of tannic acid:propylene glycol. At 5% drugloading, each of the pastes released lidocaine over a period of almost 7days (compared to EGCG formulations which released over approximately 2days). Drug release was extended by increasing the drug loading to 10%,15%, and 20%, respectively. At 20% drug loading, the tannic acid pastesreleased drug over a period of between approximately 4-5 weeks. Theorder of release was generally affected by the PG % in the paste so thatdrug release was higher as follows: 80% PG>70% PG>60% PG.

FIGS. 39A-39C show the degradation of the various lidocaine pastesreflected in FIGS. 38A-38C. The degradation curve profiles in FIGS.39A-39C generally mirror the release profiles in FIGS. 38A-38C.

Formulations including lidocaine in PG:gallate pastes results in thecreation of a partially water-insoluble waxy pellet on addition ofaqueous media. For EGCG the complexation was weak using 5% drug loadingin any paste. However, for 5% drug loading in tannic acid based pastes,the pellet lasted longer allowing controlled drug release over a periodof a week. At higher drug loadings for both EGCG and tannic acidformulations, paste degradation and drug release rates slowed as theformulations resulted in more robust pellets. In addition, increasingdrug loading created more linear drug release profiles. Increasing EGCGor tannic acid in the paste further slowed degradation and drug release.

Example 34. Use of Liquid Pharmaceutical Excipients in Gallate BasedPastes

Various additional water/soluble/miscible liquids were explored (inaddition to propylene glycol and polyethylene glycol) as excipients ingallate based pastes. This involved determining the solubility of EGCGor tannic acid in the excipient, followed by looking at the dissolutionof lidocaine at a minimum of 10% w/w followed by the addition of waterto see if the paste immediately dissolves, or if it forms a waxyimplant.

A viscosity score was established as follows: 1) Fluid—22 gauge needle;2) Semi Viscous—18 gauge needle; 3) Viscous—16 gauge needle; 4) WaxyPellet in water. Samples tested included 100 mg of each formulation atmax gallate concentration+10% lidocaine in water.

Table 2, below, shows the results for various excipients with EGCG.

TABLE 2 Paste characteristics for various excipients with EGCG.Viscosity of Pellet Solubility of Solubility of excipient with in water-Excipient EGCG in lidocaine at EGCG and intactness at with EGCGexcipient 10% loading lidocaine 24 hours Glycerol 30% Yes 2 Intact Tween80 15% Yes 3-4 50% gone Pluronic 20% Yes 3-4 50% gone I101 Labrasol 30%Almost all - 2 Intact bit grainey Transcutol  40%+ Yes 1-2 50% Cremophor20% Yes 4 Dissolved Glyceryl <20%  No 3 50% caprylate

Table 3, below, shows the results for various excipients with tannicacid.

TABLE 3 Paste characteristics for various excipients with tannic acid.Viscosity of Pellet Excipient Solubility of Solubility of excipient within water- with tannic tannic acid lidocaine at tannic and intactness atacid in excipient 10% loading lidocaine 24 hours Glycerol 30% Yes 2Intact Tween 80 15% Yes 3-4 50% gone Pluronic 20% Yes 3-4 50% gone I101Labrasol 30% Yes-very 2 Intact clear Transcutol  40%+ Yes 2 IntactCremophor 20% Yes 4 Dissolved Glyceryl <20%  No 3 50% caprylate

Aspects

1. A medical device comprising: a base structure having a surface, and acoating on the surface comprising water-insoluble therapeutic agentsolubilized within a matrix of gallate-containing compound.

2. The medical of claim 1, wherein the gallate containing compound andthe water-insoluble therapeutic agent are present at a weight ratio ofbetween 1 to 40 and 500 to 1 gallate containing compound towater-insoluble therapeutic agent

3. The medical device of claim 1, wherein the coating is free of anadditional polymer or non-polymer carrier modifying a rate of release ofthe therapeutic agent.

4. The medical device of any preceding claim, wherein the gallatecontaining compound is selected from a group consisting of epi gallocatechin gallate, tannic acid and epi catechin gallate.

5. The medical device of any preceding claim, wherein the gallatecontaining compound comprises a gallate substituted molecule such as adendrimer, a polymer, a macromolecule or a small molecule.

6. The medical device of any preceding claim, wherein the gallatecontaining compound is tannic acid.

7. The medical device of any one of claims 1 to 5, wherein the gallatecontaining compound is epi gallo catechin gallate.

8. The medical device of any preceding claim, wherein the gallatecontaining compound and the water-insoluble therapeutic agent arepresent at a weight ratio of between 30 to 1 and 500 to 1 gallatecontaining compound to water-insoluble therapeutic agent.

9. The medical device of any preceding claim, wherein thewater-insoluble therapeutic agent is contained within a matrix of thegallate containing compound and wherein the water-insoluble therapeuticagent are present at a weight ratio of between 30 to 1 and 100 to 1gallate containing compound to water-insoluble therapeutic agent.

10. The medical device of any preceding claim, wherein the implantablemedical device is an expandable device.

11. The medical device of claim 10, wherein the expandable device is aballoon.

12. The medical device of claim 10, wherein the expandable device is astent.

13. The medical device of any one of claims 1 to 8, wherein the medicaldevice is selected from the group consisting of a stent, a vascularstent, a ureteral stent, a catheter, a balloon, a balloon catheter, astent graft, a wire guide, and a cannula.

14. The medical device of any preceding claim, wherein thewater-insoluble therapeutic agent is an immunosuppressive agent, anantiproliferative agent, a microtubule stabilizing agent, arestenosis-inhibiting agent, or an inhibitor of the mammalian target ofrapamycin.

15. The medical device of claim 14, wherein the water-insolubletherapeutic agent is a taxane compound.

16. The medical device of claim 15, wherein the taxane compound ispaclitaxel or docetaxel.

17. The medical device of claim 14, wherein the therapeutic agent is amacrolide immunosuppressive agent.

18. The medical device of claim 17, wherein the macrolideimmunosuppressive agent is sirolimus, pimecrolimus, tacrolimus,everolimus, zotarolimus, novolimus, myolimus, temsirolimus, deforolimus,or biolimus.

19. The medical device of any proceeding claim, wherein the coatinglayer is adhered directly to the surface of the base structure.

20. The medical device of any one of claims 1 to 19, wherein the gallatecontaining compound is present in an amount effective to increase therate of release of the water-insoluble therapeutic agent from thecoating.

21. The medical device of any proceeding claim, wherein the coatingconsists essentially of the water-insoluble therapeutic agent and thegallate containing compound

22. The medical device of any preceding claim, wherein the gallatecontaining compound is present in an amount effective to increase therate of release of the water-insoluble therapeutic agent from the devicewhen immersed in an aqueous solution under static conditions at 37° C.

23. A medical device comprising:

a base structure, and

a composition comprising a gallate containing compound and awater-insoluble therapeutic agent, wherein the gallate containingcompound and the water-insoluble therapeutic agent are present at aweight ratio of between 1 to 40 and 500 to 1 and wherein the compositionis at least partially incorporated into the base structure.

24. The medical device of claim 23, wherein the base structure comprisesa polymeric particle or material.

25. A method for delivering a water-insoluble therapeutic agent locallyto tissue of a patient, comprising contacting a vessel wall of thepatient with the medical device of any one of claims 1 to 22, andmaintaining the device in contact with the vessel wall for a timesufficient to deliver the water-insoluble therapeutic agent to thetissue of the patient, wherein the gallate containing compound enhancesdelivery of the bioactive to the tissue.

26. A method for manufacturing a medical device, comprising: applying aflowable medium comprising liquid, a water-insoluble therapeutic agentand a gallate containing compound to a surface of an implantable medicaldevice structure or to a surface of a coating layer carried by theimplantable medical device structure; and removing liquid from themedium to form a coating layer comprising the water-insolubletherapeutic agent and the gallate containing compound.

27. The method of claim 26, wherein the gallate containing compound isepi gallo catechin gallate.

28. The method of claim 26, wherein the gallate containing compound istannic acid.

29. The method of any of claims 26 to 28, wherein the removing comprisesevaporating.

30. The method of any of claims 26 to 29, wherein the implantablemedical device is an expandable device.

31. The method of claim 30, wherein the expandable device is a balloon.

32. The method of claim 31, wherein the balloon is a vascularangioplasty balloon.

33. The method of claim 30, wherein the expandable device is a stent.

34. The method of any one of claims 26 to 33, wherein thewater-insoluble therapeutic agent is a taxane.

35. The method of claim 34, wherein the taxane is paclitaxel ordocetaxel.

36. The method of any of claims 26 to 33, wherein the water-insolubletherapeutic agent is an inhibitor of the mammalian target of rapamycin.

37. The method of claim 36, wherein the inhibitor of the mammaliantarget of rapamycin is a macrolide immunosuppressive agent.

38. The method of any one of claims 26 to 37, wherein thewater-insoluble therapeutic agent is present in the flowable medium in aweight ratio in the range of 500:1 to 1:40 with respect to the gallatecontaining compound.

39. A method for treating a patient suffering from a disease orcondition, comprising: implanting in the patient an implantable medicaldevice according to any one of claims 1 to 24 for a time sufficient todeliver a therapeutically effective amount of the water-insolubletherapeutic agent to a tissue of the patient, wherein the gallatecontaining compound enhances delivery of the water-insoluble therapeuticagent to the tissue.

40. The method of claim 39, wherein the gallate containing compound andwater-insoluble drug are encapsulated in a matrix that allows subsequentrelease of the drug, wherein the matrix comprises a composition selectedfrom the group consisting of a polymeric microsphere, a nanoparticle, afilm and a paste.

41. The method of claim 39, wherein the medical device is selected fromthe group consisting of a stent, a vascular stent, a ureteral stent, acatheter, a balloon, a balloon catheter, a stent graft, a wire guide, anembolic device and a cannula.

42. The method of claim 39, wherein the water-insoluble therapeuticagent is an immunosuppressive agent, an antiproliferative agent, amicrotubule stabilizing agent, a restenosis-inhibiting agent, or aninhibitor of the mammalian target of rapamycin.

43. The method of claim 42, wherein the water-insoluble therapeuticagent is a taxane.

44. The method of claim 43, wherein the taxane is paclitaxel.

45. The method of claim 42, wherein the water-insoluble therapeuticagent is a macrolide immunosuppressive agent.

46. The method of claim 45, wherein the macrolide immunosuppressiveagent is sirolimus, pimecrolimus, tacrolimus, everolimus, zotarolimus,novolimus, myolimus, temsirolimus, deforolimus, or biolimus.

47. A method for treating a patient suffering from a disease orcondition, comprising: administrating a composition comprising atherapeutically effective amount of a gallate containing compound and awater-insoluble therapeutic agent are present at a weight ratio ofbetween 30 to 1 and 500 to 1 gallate containing compound towater-insoluble therapeutic agent, wherein the gallate containingcompound enhances delivery of the water-insoluble therapeutic agent to atissue of the patient.

48. A method for treating a patient suffering from a disease orcondition, comprising: administering a topical preparation to the skinof a patient at an area in need of treatment, the preparation comprisinga therapeutically effective amount of a gallate containing compound anda water-insoluble drug.

49. The method of claim 48, where the drug is selected from paclitaxel,docetaxel, amphotericin, curcumin, retinoic acid, finasteride, andlidocaine.

50. The method of claim 48, where the gallate containing compound isselected from epi gallo catechin gallate and tannic acid.

51. The method of claim 48, where the preparation comprises a cream,paste, gel, or ointment.

52. A method for treating a patient suffering from a disease orcondition, comprising: administering a pharmaceutical preparation to apatient, the preparation comprising a therapeutically effective amountof a gallate containing compound and a water-insoluble drug, where theadministering comprises injecting the preparation into the patient at anarea in need of treatment, and where the preparation is formulated toform a partially water-insoluble pellet when injected into the patientthat controllably releases the drug at the area in need of treatment.

53. The method of claim 52, where the preparation is formulated torelease the drug in the body over a period of at least two days.

54. The method of claim 52, where the preparation is formulated torelease the drug in the body over a period of at least seven days.

55. The method of claim 52, where the preparation is formulated torelease the drug in the body over a period of at least two weeks.

56. The method of claim 52, where the drug is selected from paclitaxel,docetaxel, amphotericin, curcumin, retinoic acid, finasteride, andlidocaine.

57. The method of claim 52, where the gallate containing compound isselected from epi gallo catechin gallate and tannic acid.

58. The method of claim 52, where the preparation is a paste.

Although the invention has been described and illustrated with referenceto specific illustrative embodiments thereof, it is not intended thatthe invention be limited to those illustrative embodiments. Thoseskilled in the art will recognize that variations and modifications canbe made without departing from the true scope and spirit of theinvention as defined by the claims that follow. It is therefore intendedto include within the invention all such variations and modifications asfall within the scope of the appended claims and equivalents thereof.

I claim:
 1. A composition for the treatment of a medical condition,comprising: a topical drug preparation comprising a gallate containingcompound and a water-insoluble drug, where the gallate containingcompound is present in an amount effective in increasing the dermaluptake of the drug, where the gallate containing compound is present inan amount by weight equal to or greater than the amount by weight of thewater-insoluble drug.
 2. The composition of claim 1, where the gallatecontaining compound is selected from the group consisting of epi gallocatechin gallate and tannic acid.
 3. The composition of claim 1, wherethe drug is selected from paclitaxel, docetaxel, amphotericin, curcumin,retinoic acid, finasteride, and lidocaine.
 4. The composition of claim1, where the drug has a molecular weight greater than 500 Daltons. 5.The composition of claim 1, further comprising a solubilizing excipient.6. The composition of claim 1, where the topical drug preparationcomprises a eutectic solution.
 7. The composition of claim 1, where theweight ratio of gallate containing compound:water-insoluble drug is inthe range of 200:1 to 1:1, 200:1 to 5:1, 200:1 to 10:1, 200:1 to 30:1,200:1 to 50:1, 100:1 to 1:1, 100:1 to 5:1, 100:1 to 10:1, 100:1 to 30:1,100:1 to 50:1, 50:1 to 1:1, 50:1 to 5:1, 10:1 to 1:1, or 10:1 to 5:1. 8.The composition of claim 1, where the topical preparation comprises acream, paste, gel, or ointment.
 9. The composition of claim 1, where thetopical preparation comprises a preblended solid or semi solid matrix ofthe gallate containing compound and the drug.
 10. The composition ofclaim 1, where the gallate containing compound and the drug arepredispersed in one of a membrane, a hydrogel, an electrospun film, or askin dressing.
 11. The composition of claim 1, where the preparation isnonaqueous.
 12. A composition for the treatment of a medical condition,comprising: a nonaqueous pharmaceutical preparation comprising a gallatecontaining compound and a water-insoluble drug, where the preparation isformulated to form a partially water-insoluble mass when placed in anaqueous medium, that gradually releases the drug into the aqueous mediumin a controlled manner.
 13. The composition of claim 12, where thepreparation is formulated to release the drug into the aqueous mediumover a period of at least two days.
 14. The composition of claim 12,where the preparation is formulated to release the drug into the aqueousmedium over a period of at least two weeks.
 15. The composition of claim12, where the gallate containing compound is present in an amounteffective in increasing the solubility of the water-insoluble drug in anaqueous medium.
 16. The composition of claim 12, where the gallatecontaining compound is present in an amount by weight equal to orgreater than the amount by weight of the water-insoluble drug.
 17. Thecomposition of claim 12, where the gallate containing compound isselected from the group consisting of epi gallo catechin gallate andtannic acid.
 18. The composition of claim 12, where the drug is selectedfrom paclitaxel, docetaxel, amphotericin, curcumin, retinoic acid,finasteride, and lidocaine.
 19. The composition of claim 12, furthercomprising a solubilizing excipient selected from the group consistingof glycerol, poloxamer, propylene glycol, and polyethylene glycol.